Renin inhibiting N-(2-amino-2-oxoethyl)butanediamide derivatives

ABSTRACT

Disclosed herein are compounds of the formula:A-N(R1)C(O)CH2CHR2C(O)-Bwherein A is R3R4NC(O)CH2 wherein, for example, R3 is hydrogen or alkyl and R4 is hydrogen, alkyl or a substituted alkyl such as 2-(2-pyridinyl)ethyl, or R3 and R4 together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino, morpholino or thiomorpholino; R1 is, for example, benzyl, alkyl or a substituted alkyl such as cyclohexylmethyl; R2 is, for example, alkyl, cycloalkylmethyl, 1H-imidazol-4-ylmethyl, 4-thiazolylmethyl or (2-amino-4-thiazolyl)methyl; and B is a renin substrate transition state analog, for example, [1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]amino. The compounds inhibit renin activity and are indicated for the treatment of hypertension and congestive heart failure.

This application is a continuation-in-part of prior U.S. Ser. No.07/951,478, filed Sep. 25, 1992, and now abandoned.

FIELD OF INVENTION

This invention relates to compounds exhibiting renin inhibitingproperties, to processes for producing the compounds, to pharmaceuticalcompositions thereof, to processes and intermediates for preparing thecompounds and to methods of treating renin-dependent hypertension andcongestive heart failure.

BACKGROUND OF THE INVENTION

The physiological role of the renin-angiotensin system is to regulateblood pressure and to maintain sodium and volume homeostasis. The keyevents in this system are the conversion of the polypeptideangiotensinogen to the decapeptide angiotensin I (AI) and the subsequentcleavage of the latter to give the octapeptide angiotensin II (AII). Thelatter peptide is a potent vasoconstrictor and a potentiator ofaldosterone release. Due to potent pressor effects, AII plays asignificant role in hypertension and as such has been the target for thedevelopment of antihypertensive agents.

One approach to finding such agents is to search for potent inhibitorsof the angiotensin converting enzyme. Inter alia, the latter enzymecatalyzes the conversion of AI to AII. This approach has met withsuccess and a number of such agents are used therapeutically to treathypertension. Another approach is to find specific inhibitors of renin,an aspartyl protease which cleaves angiotensinogen to AI. Sinceangiotensinogen is the only known natural substrate for renin, thisapproach has the desirable feature of being aimed at a potentialantihypertensive agent with a single mode of action.

In the pursuit of this goal, a great deal of attention has been given todesigning renin inhibitors which mimic the natural substrateangiotensinogen. Much of this effort has been focused on the design ofanalogous substrates incorporating therein a non-cleavable mimic (i.e. atransition state analog) of the renin cleavage site (i.e. Leu-Val) ofhuman angiotensinogen. As a result, a number of potent renin inhibitorshave been identified in the laboratory, and the ability of renininhibitors to lower blood pressure and to reduce plasma renin activityhas now been demonstrated in the clinic. For a recent review on renininhibitors, see W. J. Greenlee, Medical Research Reviews, 10, 173(1990). Nevertheless, progress toward obtaining the ideal renininhibitor continues to be plagued with problems of low oral absorption,limited bioavailability and rapid elimination, mainly due to thepeptidic nature of the inhibitors presently under investigation. Hence,there is a need for a readily administered, effective renin inhibitor.

The renin inhibitors of the present application belong to the class oftransition state analog inhibitors of renin. They are characterized byhaving a N-(amidomethyl)succinamoyl moiety incorporated into theirstructure. This feature, in combination with their non-peptidiccharacter and their relatively lower molecular weight, apparentlycontribute beneficially to the stability, absorption and bioavailabilityof the inhibitors. Another feature of the present inhibitors is theirrelative specificity for renin as compared to other aspartyl proteases.

The following references exemplify past efforts that have been made inthe search for renin inhibitors with improved characteristics:

W. J. Greenlee et al., European patent application 278 158, publishedAug. 17, 1988;

A. A. Patchett et al., U.S. Pat. No. 4,839,357, issued Jun. 13, 1989;

D. J. Kempf et al., European patent application 402 646, published Dec.19, 1990;

P. D. Williams et al., U.S. Pat. No. 5,001,113, issued Mar. 19, 1991;

H. Heitsch et al., Canadian patent application 2,025,093, published Mar.13, 1991;

W. J. Greenlee et al., U.S. Pat. No. 5,006,511, issued Apr. 9, 1991;

P. D. Williams, Canadian patent application 5 2,034,524, published Jul.20,1991;

H. N. Weller and D. E. Ryono, U.S. Pat. No. 5,055,466, issued Oct. 8,1991; and

S. H. Rosenberg et al., U.S. Pat. No. 5,063,208, issued Nov. 5, 1991.

SUMMARY OF THE INVENTION

The compounds of the present application are represented by formula 1

    A--N(R.sup.1)C(O)CH.sub.3 CH(R.sup.2)C(O)--B               (1)

wherein A is R³ R⁴ NC(O)CH₂ wherein

(a) R³ is hydrogen or lower alkyl and R⁴ is hydrogen, lower alkyl orlower alkyl monosubstituted with lower cycloalkyl, phenyl, or aheterocylic ring (hereinafter designated as "Het") which is anunsubstituted, monosubstituted or disubstituted, five- or six-memberedring containing one or two heteroatoms selected from the groupconsisting of N, O and S, and wherein each substituent is selectedindependently from the group consisting of lower alkyl, lower alkoxy,halo, amino or lower alkylamino; or

(b) R³ is lower alkyl and R⁴ is R⁵ R⁶ N-Alk wherein R⁵ and R⁶ each ishydrogen or lower alkyl and Alk is a divalent alkyl radical derived bythe removal of two hydrogen atoms of a straight or branched chainhydrocarbon containing from one to six carbon atoms; or

(c) R³ is lower alkyl and R⁴ is R^(5A) R^(6A) NCH₂ CH₂ wherein R^(5A) islower alkyl and R^(6A) is piperidinocarbonyl, morpholinocarbonyl,thiomorpholinocarbonyl, piperazinocarbonyl or 4-(loweralkyl)-1-piperazinylcarbonyl; or

(d) R³ is lower alkyl and R⁴ is QC(O)(CH₂)_(m) wherein Q is piperidino,morpholino, thiomorpholino, piperazino or 4-(lower alkyl)-1-piperazinyland m is the integer 1 or 2; or

(e) R³ is lower alkyl and R⁴ is lower alkoxy; or

(f) R³ and R⁴ together with the nitrogen atom to which they are attachedform a pyrrolidino, piperidino, 4-hydroxy-l-piperidinyl, 4-[(loweralkoxy)-(lower alkoxy)]-1-piperidinyl, morpholino, thiomorpholino,piperazino or 4-(lower alkyl)-1-piperazinyl;

R¹ is (1-8C)alkyl or lower alkyl monosubstituted with lower cycloalkyl,1-(lower alkyl)-(lower cycloalkyl), (bicyclo[2.2.1]hept-2-yl)methyl,phenyl, 2-(lower alkyl)phenyl, 2-(lower alkoxy)phenyl, 2-halophenyl,4-(lower alkyl)phenyl, 4-(lower alkoxy)phenyl, 4-halophenyl,3,5-di(lower alkyl)phenyl, (3,4-methylenedioxy)phenyl, 1-naphthyl,2-naphthyl or Het wherein Het is as defined hereinabove;

R² is lower alkyl, (lower cycloalkyl)methyl, benzyl or Het-CH₂ whereinHet is as defined hereinabove; and

B is a transition state analog of the formula NHCH(R⁷)CH(OH)--Z whereinR⁷ is lower alkyl, (lower cycloalkyl)methyl, benzyl, [4-(loweralkyl)phenyl]methyl, [4-(lower alkoxy)phenyl]methyl, or(4-halophenyl)methyl, and Z is lower alkyl, lower cycloalkyl, (lowercycloalkyl)methyl, C(O)OR⁸ wherein R⁸ is lower alkyl, the radical offormula 2 ##STR1## wherein R⁹ is lower alkyl and R¹⁰ and R¹¹ each ishydrogen or lower alkyl, [(1-methyl-1H-tetrazol-5-yl)thio]methyl orCH(OH)R¹² wherein R¹² is lower alkyl or lower cycloalkyl, with theprovisos (1) that the asymmetric carbon atom bearing R⁷ has the (S)configuration, (2) that when Z is lower alkyl, lower cycloalkyl, (lowercycloalkyl)methyl or the radical of formula 2 as defined hereinabovethen the asymmetric carbon atom bearing the hydroxyl in theNHCH(R⁷)CH(OH) radical has the (S) configuration,

(3) that when Z is C(O)OR⁸ wherein R⁸ is lower alkyl, or when Z is[(1-methyl-1H-tetrazol-5-yl)thio]methyl, then the asymmetric carbon atombearing the hydroxyl in the NHCH(R⁷)CHOH radical has the (R)configuration, and (4) that when Z is CH(OH)R¹² wherein R¹² is loweralkyl or lower cycloalkyl then the asymmetric carbon atoms bearing thehydroxyls in the NHCH(R⁷)CH(OH) and Z radicals have respectively the (R)and (S) configuration;

with the additional proviso that the carbon atom bearing R² has the (R)configuration, except when R² is CH₂ -Het wherein Het has a nitrogenatom at the point of attachment, and/or Het contains a sulfur atom nextto the atom (C or N) at the point of attachment, of the Het to themethylene (CH₂), then in the instance of this exception the carbon atombearing R² has the (S) configuration; or a therapeutically acceptableacid addition salt thereof.

A preferred group of the compounds of the present application isrepresented by formula 1 wherein A is R³ R⁴ NC(O)CH₂ wherein

(a) R³ is lower alkyl and R⁴ is lower alkyl or lower alkylmonosubstituted with phenyl or Het wherein Het is as definedhereinabove;

(b) R³ is lower alkyl and R⁴ is R⁵ R⁶ N-Alk wherein R⁵ and R⁶ each islower alkyl and Alk is as defined hereinabove;

(c) R³ is lower alkyl and R⁴ is R^(5A) R^(6A) NCH₂ CH₂ wherein R^(5A) islower alkyl and R^(6A) is piperidinocarbonyl, morpholinocarbonyl or4-methyl-1-piperazinylcarbonyl; or

(d) R³ is lower alkyl and R⁴ is 2-morpholino-2-oxoethyl,3-morpholino-3-oxopropyl or 3-(4-methyl-1-piperazinyl)-3-oxopropyl; or

(e) R³ is lower alkyl and R⁴ is lower alkoxy; or

(f) R³ and R⁴ together with the nitrogen atom to which they are attachedform a pyrrolidino, piperidino, 4-hydroxy-1-piperidinyl,4-(methoxymethoxy)-1-piperidinyl, morpholino, thiomorpholino or4-methyl-1-piperazinyl;

R¹ is (1-8C)alkyl or lower alkyl monosubstituted with lower cycloalkyl,1-(lower alkyl)-(lower cycloalkyl), (bicyclo[2.2.1]hept-2-yl)methyl,phenyl, 2-methylphenyl, 2-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl,4-chlorophenyl, 4-fluorophenyl, 3,5-dimethylphenyl,(3,4-methylenedioxy)phenyl, 1-naphthyl, 2-naphthyl or Het wherein Het isas defined hereinabove;

R² is lower alkyl, (lower cycloalkyl)methyl, benzyl,1H-imidazol-2-ylmethyl, 1H-imidazol-4-ylmethyl,(1-methyl-1H-imidazoyl-4-yl)methyl, 2-thienylmethyl, 2-oxazolylmethyl,4-oxazolylmethyl, 2-thiazolylmethyl, 4-thiazolylmethyl,(2-methyl-4-thiazolyl)methyl, (2-amino-4-thiazolyl)methyl,[2-(methylamino)-4-thiazolyl]methyl, 2-pyridinylmethyl or3-pyridinylmethyl; and B is as defined in the last instance; or atherapeutically acceptable acid addition salt thereof.

A more preferred group of compounds is represented by formula 1 whereinA is R³ R⁴ NC(O)CH₂ wherein R³ is methyl, ethyl or propyl and R⁴ ismethyl, ethyl, propyl 1,1-dimethylethyl, 2-(dimethylamino)ethyl,2-(diethylamino)ethyl, or Het-(CH₂)_(n) wherein Het is 2-pyrrolyl,2-furanyl, 2-thienyl, 1H-imidazol-4-yl, 2-isoxazolyl, 2-thiazolyl,4-thiazolyl, 2-amino-4-thiazolyl, morpholino, 4-methyl-1-piperazinyl,2-pyridinyl, 3-pyridinyl, 4-pyridinyl or 2-pyrimidinyl and n is theinteger 1, 2 or 3; or R³ is methyl and R⁴ is2-[methyl(morpholinocarbonyl)amino]ethyl or2-{methyl[(4-methyl-1-piperazinyl)carbonyl]amino}ethyl; or R³ is methyland R⁴ is 3-morpholino-3-oxopropyl or3-(4-methyl-1-piperazinyl)-3-oxopropyl; or R³ is methyl and R⁴ ismethoxy; or R³ and R⁴ together with the nitrogen to which they areattached form a pyrrolidino, piperidino, 4-hydroxy-1-piperidinyl,4-(methoxymethoxy)-1-piperidinyl, morpholino or 4-methyl-1-piperazinyl;

R¹ is 2-methylpropyl, 2-ethylbutyl, 1-propylbutyl, 2-propylpentyl,cyclopentylmethyl, 2-cyclopentylethyl, cyclohexylmethyl,(S)-1-cyclohexylethyl, 2-cyclohexylethyl, cycloheptylmethyl,(1-methylcyclohexyl)methyl, (1-methylcycloheptyl)methyl,(bicyclo[2.2.1]hept-2-yl)methyl, benzyl, (S)-1-phenylethyl,2-phenylethyl, (R or S)-2-phenylpropyl, 2-methyl-2-phenylpropyl,3-phenylpropyl, (2-fluorophenyl)methyl, (2-methylphenyl)methyl,(4-methoxyphenyl)methyl, (4-chlorophenyl)methyl, (4-fluorophenyl)methyl,(3,5-dimethylphenyl)methyl, 1-phenyl)methyl, 1-naphthylmethyl,(S)-[1-(1-naphthyl)ethyl], 2-naphthylmethyl, 2-pyrrolylmethyl,1H-imidazol-2-ylmethyl, 1H-imidazol-4-ylmethyl, 2-pyridinylmethyl,3-pyridinylmethyl, 2-furanylmethyl, 3-furanylmethyl 2-thienylmethyl,(3-methyl-2-thienyl)methyl, 2-oxazolylmethyl, 4-oxazolylmethyl,2-thiazolylmethyl or (2-amino-4-thiazolyl)methyl; R² is propyl,2-methylpropyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexyl-methyl,benzyl, 1H-imidazol-2-ylmethyl, 1H-imidazol-4-ylmethyl,(1-methyl-1H-imidazol-4-yl)methyl, 2-thienylmethyl, 2-oxazolylmethyl,4-oxazolylmethyl, 2-thiazolylmethyl, 4-thiazolylmethyl,(2-methyl-4-thiazolyl)methyl, (2-amino-4-thiazolyl)methyl,[2-(methylamino)-4-thiazolyl]methyl, 2-pyridinylmethyl or3-pyridinylmethyl; and B is[1(S)-(2-methylpropyl)-2(S)-hydroxy-5-methylhexyl]amino,[1(S)-(cyclohexylmethyl)-2(S)-hydroxy-5-methylhexyl]amino,[1(S)-[(4-methoxylphenyl)methyl]-2(S)-hydroxy-5-methylhexyl]amino,[1(S)-(cyclohexylmethyl)-2(S)-hydroxy-4-methylpentyl]amino,[1(S)-(cyclohexylmethyl)-2(S)-hydroxy-(3-cyclopropylpropyl)]amino,[1(S)-(2-methylpropyl)-2(R),3(S)-dihydroxy-5-methylhexyl]amino,[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]amino,{1(S)-[(4-methoxyphenyl)methyl]-2(R),3(S)-dihydroxy-5-methylhexyl}amino,[1(S)-(2-methylpropyl)-2(R),3(S)-dihydroxy-(3-cyclopropylpropyl)]amino,[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-(3-cyclopropylpropyl)]amino,[1(S)-(phenylmethyl)-2(R),3(S)-dihydroxy-(3-cyclopropylpropyl)]amino,{1(S)-[(4-methoxyphenyl)methyl]-2(R),3(S)-dihydroxy-(3-cyclopropylpropyl)]amino,[1(S)-(cyclohexylmethyl)-2(R)-hydroxy-3-(1-methylethoxy)-3-oxopropyl]amino,[1(S)-(cyclohexylmethyl)-2(S)-hydroxy-2-(1,5,5-trimethyl-2-oxopyrrolidin-3(S)-yl)ethyl]aminoor{1(S)-(cyclohexylmethyl)-2(R)-hydroxy-3-[(1-methyl-1H-tetrazol-5-yl)thio]propyl}amino;or a therapeutically acceptable acid addition salt thereof.

A most preferred group of the compound is represented by formula 1wherein A is R³ R⁴ NC(O)CH₂ wherein R³ is methyl and R⁴ is methyl,2-(dimethylamino)ethyl, 2-(diethylamino)ethyl, 2-(2-pyrrolyl)ethyl,2-(2-furanyl)ethyl, 2-(1H-imidazol-2-yl)ethyl,2-(1H-imidazol-4-yl)ethyl, 2-(2-thiazolyl)ethyl, 2-morpholinoethyl,2-(2-pyridinyl)ethyl, 2-(3-pyridinyl)ethyl, 2-(4-pyridinyl)ethyl or2-(2-pyrimidinyl)ethyl; or R³ is methyl and R⁴ is2-[methyl(morpholinocarbonyl)amino]ethyl; or R³ is methyl and R⁴ ismethoxy; or R³ and R⁴ together with the nitrogen atom to which they areattached form a pyrrolidino, piperidino, 4-hydroxy-1-piperidinyl,4-(methoxymethoxy)-1-piperidinyl, morpholino or 4-methyl-1-piperazinyl;R¹ is 2-ethylbutyl, 1-propylbutyl, 2-propylpentyl, cyclopentylmethyl,2-cyclopentylethyl, cyclohexylmethyl,(S)-1-cyclohexylethyl,cycloheptylmethyl, (bicyclo[2.2.1]hept-2-yl)methyl, benzyl,(S)-1-phenylethyl, 2-phenylethyl, (S)-2-phenylpropyl,(R)-2-phenylpropyl, (2-fluorophenyl)methyl, (2-methylphenyl)methyl,(3,5-dimethylphenyl)methyl, 1-naphthylmethyl, 2-furanylmethyl,3-furanylmethyl, 2-thienylmethyl, (3-methyl-2-thienyl)methyl or2-thiazolylmethyl; R² is propyl, cyclopropylmethyl,1H-imidazol-4-ylmethyl, (1-methyl-1H-imidazol-4-yl)methyl,2-thienylmethyl, 2-oxazolylmethyl, 4-oxazolylmethyl, 2-thiazolylmethyl,4-thiazolylmethyl, (2-methyl-4-thiazolyl)methyl or(2-amino-4-thiazolyl)methyl; and B is[1(S)-(cyclohexylmethyl)-2(S)-hydroxy-5-methylhexyl]amino,[1(S)-(cyclohexylmethyl)-2(S)-hydroxy-(3-cyclopropylpropyl)]amino,[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-(3-cyclopropylpropyl)]amino,[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]amino,[1(S)-(cyclohexylmethyl)-2(R)-hydroxy-3-(1-methylethoxy)-3-oxopropyl]aminoor[1(S)-(cyclohexylmethyl)-2(S)-hydroxy-2-(1,5,5-trimethyl-2-oxopyrrolidin-3(S)-yl)ethyl]amino;or a therapeutically acceptable acid addition salt thereof.

Included within the scope of this invention is a pharmaceuticalcomposition for treating renin-dependent hypertension comprising acompound of formula 1, or a therapeutically acceptable acid additionsalt thereof, and a pharmaceutically acceptable carrier.

Also included in this invention is a method of treating renin-dependenthypertension or congestive heart failure in a mammal comprisingadministering thereto a blood pressure-lowering effective amount of thecompound of formula 1, or a therapeutically acceptable acid additionsalt thereof.

Processes for preparing the compounds of formula 1 are describedhereinafter.

DETAILS OF THE INVENTION

GENERAL

With reference to the instances where (R) or (S) is used to designatethe configuration of a radical, e.g. R¹ of the compound of formula 1,the designation is done in the context of the compound and not in thecontext of the radical alone.

The term "Alk" as used herein means a divalent alkyl radical derived bythe removal of two hydrogen atoms from a straight or branched chainaliphatic hydrocarbon containing from one to six carbon atoms andincludes, for example, --CH₂ CH₂ --, --CH₂ CH₂ CH₂ --, --CH(CH₃)CH₂ CH₂-- and --(CH₂)₆ --.

The term "lower alkyl" as used herein, either alone or in combinationwith another radical, means straight chain alkyl radicals containing oneto four carbon atoms and branched chain alkyl radicals containing threeto four carbon atoms and includes methyl, ethyl, propyl, butyl,1-methylethyl, 1-methylpropyl, 2-methylpropyl and 1,1-dimethylethyl. Theterm "(1-8C)alkyl" as used herein means straight and branched chainalkyl radicals containing from one to eight carbon atoms and includesethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1-ethylpropyl,2-ethylbutyl, 2-propylpentyl and the like.

The term "lower cycloalkyl" as used herein, either alone or incombination with a radical, means saturated cyclic hydrocarbon radicalscontaining from three to ten carbon atoms and includes cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The term "lower alkoxy" as used herein means straight chain alkoxyradicals containing one to four carbon atoms and branched chain alkoxyradicals containing three to four carbon atoms and includes methoxy,ethoxy, propoxy, 1-methylethoxy, butoxy and 1,1-dimethylethoxy. Thelatter radical is known commonly as tert-butoxy.

The term "halo" as used herein means a halo radical selected from bromo,chloro, fluoro or iodo.

The term "Het" as used herein means a monovalent radical derived byremoval of a hydrogen from a five- or six-membered saturated orunsaturated heterocycle containing from one to two heteroatoms selectedfrom nitrogen, oxygen and sulfur. Optionally, the heterocycle may bearone or two substituents; for example, lower alkyl, lower alkoxy, halo,amino or lower alkylamino. Examples of suitable heterocycles andoptionally substituted heterocycles include pyrrolidine,tetrahydrofuran, thiazolidine, pyrrole, 1H-imidazole,1-methyl-1H-imidazole, pyrazole, furan, thiophene, 3-methylthiophene,oxazole, isoxazole, thiazole, 2-methylthiazole, 2-aminothiazole,2-(methylamino)thiazole, piperidine, 1-methylpiperazine, 1,4-dioxane,morpholine, pyridine, pyrimidine and 2,4-dimethylpyrimidine.

The term "coupling agent" as used herein means an agent capable ofeffecting the dehydrative coupling of a carboxy group of one compoundwith a free amino group of another compound to form an amide bondbetween the reactants. The agents promote or facilitate the dehydrativecoupling by activating the carboxy group. Descriptions of such couplingagents and activated groups are included in general textbooks of peptidechemistry; for instance, E. Schroder and K. L. Lubke, "The Peptides",Vol. 1, Academic Press, New York, N.Y., 1965, pp 2-128, and "ThePeptides: Analysis, Synthesis, Biology", E. Grass et al., Eds., AcademicPress, New York, N.Y., U.S.A., 1979-1987, Volumes 1 to 9. Examples ofsuitable coupling agents are 1,1'-carbonyldiimidazole orN,N'-dicyclohexylcarbodiimide. Other examples are 1-hydroxybenzotriazolein the presence of N,N'-dicyclohexylcarbodiimide orN-ethyl-N'-[(3-dimethylamino)propyl]carbodiimide. A very practical anduseful coupling agent is the commercially available(benzotriazol-1-yloxy)tris(dimethylamino)-phosphoniumhexafluorophosphate, either by itself or in the presence of1-hydroxybenzotriazole. Still another very practical and useful couplingagent is the commercially available2-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate.

The term "pharmaceutically acceptable carrier" as used herein means anon-toxic, generally inert vehicle for the active ingredient, which doesnot adversely affect the ingredient.

The term "effective amount" as used herein means a predetermined amountof the compound of formula 1 sufficient to lower blood pressure on beingadministered to a mammal.

Process

In general, the compounds of formula 1 are prepared by known methodsusing reaction conditions which are known to be suitable for thereactants. Description of the methods are found in standard textbookssuch as "Annual Reports In Organic Synthesis--1990", K. Turnbull et al.,Eds, Academic Press, Inc., San Diego, Calif., U.S.A., 1990 (and thepreceding annual reports), "Vogel's Textbook Of Practical OrganicChemistry", B. S. Furniss et al., Eds, Longman Group Limited, Essex, UK,1986, and "The Peptides: Analysis, Synthesis, Biology", E. Grass et al.,Eds, Academic Press, New York, N.Y., U.S.A., 1979-1987, Volumes 1 to 9.

Since the compounds of formula 1 contain two amide bonds, a convenientand practical approach to preparing the compounds is based on thestep-wise coupling of the appropriate fragments, i.e. precursors for theamide bond fermations.

A common feature of the coupling of the fragments, which involves thereaction of a free amino function of one fragment with a free carboxyfunction of another fragment, is the protection of competing reactivesites, if present, on the fragments. Such protection is provided by theuse of known protective groups which will prevent a chemical reactionfrom occurring at the competing site during the coupling step and whichcan ultimately be removed after completion of the coupling to afford thedesired product. The protective groups and the deprotecting agents forremoving the group are selected according to conventional practice. SeeJ. W. Greene and P. G. M. Wuts, "Protective Groups In OrganicSynthesis", 2nd ed., John Wiley & Sons, Inc., New York, N.Y., U.S.A.,1991 for a full description of protective groups and deprotectiveagents.

More explicitly, a process for preparing the compounds of formula 1,involving the stepwise coupling of appropriate fragments in whichcompeting reactive sites, if present, are protected by suitableprotective groups, comprises:

(a) coupling a monoprotected dicarboxylic acid of formula 2

    W.sup.1 --C(O)CH.sub.2 CH(R.sup.2)C(O)OH                   2

wherein W¹ is a carboxy protecting group and R² is as definedhereinbefore with an amine of formula H--B wherein B is as definedherein to obtain the corresponding protected amido acid of formula 3

    W.sup.1 --C(O)CH.sub.2 CH(R.sup.2)C(O)--B                  3

wherein W¹, R² and B are as defined hereinbefore;

(b) reacting the latter compound with a deprotecting agent to obtain thecorresponding amido acid of formula 4

    HO--C(O)CH.sub.2 CH(R.sup.2)C(O)--B                        4

wherein R² and B are as defined hereinbefore; and

(c) coupling the latter amido acid with an amine of formula ANH(R¹)wherein A and R¹ are as defined hereinbefore; and, if required,eliminating any protective groups on the instant product used to protectcompeting reactive sites during the process, to obtain the correspondingcompound of formula 1.

Alternatively, the compounds of formula 1 can be prepared by ananalogous process comprising:

(d) coupling an amine of formula ANH(R¹) in which A and R¹ are asdefined hereinbefore with a monoprotected dicarboxylic acid of formula 5

    HO--C(O)CH.sub.2 CH(R.sup.2)C(O)--W.sup.2                  5

wherein R² is as defined herein and W² is a carboxy protective group toobtain the corresponding protected amido acid of formula 6

    A--N(R.sup.1)C(O)CH.sub.2 CH(R.sup.2)C(O)--W.sup.2         6

wherein A, R¹, R² and W² are as defined hereinbefore;

(e) reacting the latter compound with a deprotecting agent to obtain thecorresponding amido acid of formula 7

    A--N(R.sup.1)C(O)CH.sub.2 CH(R.sup.2)C(O)--OH              7

wherein A, R¹ and R² are as defined hereinbefore; and

(f) coupling the latter amido acid with an amine of formula H--B whereinB is as defined hereinbefore; and, if required, eliminating anyprotective groups on the instant product used to protect competingreactive sites during the process, to obtain the corresponding compoundof formula 1.

Note that with respect to the preceding compounds of formulae 2 to 7,inclusive, the aformentioned provisos regarding the stereochemistry of Band R² apply as well to the corresponding carbon atoms of thesecompounds.

Examples of suitable carboxy protective groups for the precedingprocesses are phenylmethoxy(benzyloxy), (4-nitrophenyl)methoxy,9-fluorenylmethoxy and tert-butoxy. Note also that a4-substituted-2-oxazolidinone group, arising from the use of an "Evans'chiral auxiliary" to prepare the monoprotected dicarboxylic acids 2 and5, as described hereinafter, can be used as a carboxy protective group.

The requisite starting materials of formula 2 and formula 5 can beprepared by processes designed to give the desired stereochemistry.Convenient and practical processes for preparing the starting materialsinvolve the application of the stereoselective alkylation method of D.A. Evans et al., J. Amer. Chem. Soc., 103, 2127 (1981) and J. Amer.Chem. Soc., 104, 1737 (1982). Such a process is illustrated by thefollowing scheme directed to the preparation of the protected carboxylicacid 2 wherein R² is as defined herein, W¹ is tert-butoxy orphenylmethoxy (the carboxy protective group) and U is 1-methylethyl orbenzyl. ##STR2##

Accordingly, the chiral imide 8 is alkylated with tert-butylα-bromoacetate or benzyl α-bromoacetate to afford the protected imide 9.Subsequent reaction of the latter compound with lithiumhydroxide-hydrogen peroxide gives the monoprotected dicarboxylic acid offormula 2 in which R² and W¹ are as defined in the last instance.

In turn, the chiral imide 8 can be prepared by acylating the "Evans'chiral auxiliary", (S)-4-(1-methylethyl)-2-oxazolidinone or(S)-4-(phenylmethyl)-2-oxazolidinone, with the corresponding acid offormula R² CH₂ COOH or a precursor acid capable of being transformed tothe chiral imide 9.

An analogous process can be used to prepare the monoprotecteddicarboxylic acids of formula 5. A convenient and practical process isrealized for example by simply removing the carboxy protective group W¹from the previously noted protected amide 9 whereby the desiredmonoprotected dicarboxylic acid of formula 5 is obtained. In thisinstance, the chiral auxiliary, i.e. the N-substituted4(S)-(1-methylethyl)-2-oxazolidinone, assumes a new role as the carboxyprotective group W².

Processes for preparing the monoprotected dicarboxylic acids of formulae2 and 5 are illustrated in the examples hereinafter.

The amines of formula ANH(R¹) in which A and R¹ are as defined hereinare either known or can be prepared by standard methods for preparingamines, see for example S. G. Wilkinson in "Comprehensive OrganicChemistry, D. Barton and W. D. Ollis, Eds, Pergamon Press, Oxford, UK,Vol. 2, pp 3-302, 1979. Typical preparations of various amines offormula A--H are described in the examples.

The amines of formula H--B in which B is as defined hereinbefore areknown, having been described by K. Nakano et al., European patentapplication 281 316, published Sep. 7, 1988, J. R. Luly et al., U.S.Pat. No. 4,845,079, issued Jul. 4, 1989, B. Quirico et al., Europeanpatent application 332 008, published Sep. 13, 1989, K. Hemmi et al.,U.S. Pat. No. 4,963,530, issued Oct. 16, 1990, P. D. Williams et al., J.Med. Chem., 34, 887 (1991) and F. Matsuda et al., Bull. Chem. Soc. Jpn.,65, 360 (1992).

In the instance where a particular compound of formula 1 has a residuewhich functions as a base, the compound can be obtained in the form of atherapeutically acceptable acid addition salt. Examples of such saltsare those with organic acids, e.g. acetic, lactic, succinic, benzoic,salicylic, methanesulfonic or p-toluenesulfonic acid, as well aspolymeric acids such as tannic acid or carboxymethyl cellulose, and alsosalts with inorganic acids such as hydrohalic acids, e.g. hydrochloricacid, or sulfuric acid, or phosphoric acid. If desired, a particularacid addition salt is converted into another acid addition salt, such asa non-toxic, pharmaceutically acceptable salt, by treatment with theappropriate ion exchange resin in the manner described by R. A.Boissonnas et al., Helv. Chim. Acta, 43, 1849 (1960).

In general, the therapeutically acceptable salts of the compounds offormula 1 are biologically fully equivalent to the peptides themselves.

Biological Aspects

The compounds of formula 1 possess the ability to inhibit reninactivity. The renin inhibiting activity and enzyme specificity of thecompounds can be demonstrated in standard pharmacological tests such asthose described by J. R. Luly et al., Biochem. Biophys. Res. Comm., 143,44 (1987).

In vitro renin inhibiting activity for the compounds has beendemonstrated in the plasma renin assay, see example 6 hereinafter.

Primates (e.g. marmosets, cynomolgus monkeys and baboons) are apreferred species for demonstrating in vivo activity for renininhibitors, because there is substantial homology in the sequence ofprimate renin and human renin. In this connection, compounds of thisinvention have shown blood pressure lowering effects when the compoundswere administered intravenously or orally to sodium-depleted cynomolgusmonkeys, pretreated 18 hours before with an intramuscular injection (2.5mg/kg) of furosemide to stimulate endogenous renin secretion.

Accordingly, the compounds are indicated for the diagnosis, prophylaxisand treatment of renin-associated hypertension in mammals includinghumans, primates, horses and dogs. The compounds also can be used fortreating congestive heart failure in mammals including humans, primates,horses and dogs. For the latter purposes or indications, the compoundscan be administered orally or parenterally in a vehicle comprising oneor more pharmaceutically acceptable carriers, the proportion of which isdetermined by the solubility and chemical nature of the compounds,chosen route of administration and standard biological practice. Fororal administration, the compound can be formulated in unit dosage formssuch as capsules or tablets each containing a predetermined amount ofthe active ingredient, ranging from about 25 to 250 mg, in apharmaceutically acceptable carrier.

For parenteral administration, the compound of formula 1 is administeredby either intravenous, subcutaneous or intramuscular injection, incompositions with pharmaceutically acceptable vehicles or carriers. Foradministration by injection, it is preferred to use the compound insolution in a sterile aqueous vehicle which may also contain othersolutes such as buffers or preservatives as well as sufficientquantities of pharmaceutically acceptable salts or of glucose to makethe solution isotonic.

Suitable vehicles or carriers for the above noted formulations can befound in standard pharmaceutical texts, e.g. in "Remington'sPharmaceutical Sciences", 18th ed, Mack Publishing Company, Easton, Pa.,1990.

The dosage of the compound will vary with the form of administration andthe particular active agent chosen. Furthermore, it will vary with theparticular host under treatment. Generally, treatment is initiated withsmall dosages substantially less than the optimum dose of the compound.Thereafter, the dosage is increased by small increments until theoptimum effect under the circumstances is reached. In general, thecompound is most desirably administered at a concentration level thatwill lower blood pressure without causing any harmful or deleteriousside effects.

For oral administration, the compound is administered in the range of1.0 to 50 mg per kilogram of body weight per day, with a preferred rangeof 1.0 to 30 mg per kilogram per day.

With reference to systemic administration, the compound of formula 1 isadministered at a dosage of 0.1 mg to 5.0 mg per kilogram of body weightper day, although the aforementioned variations will occur. However, adosage level that is in the range of from about 0.1 mg to 1.0 mg perkilogram of body weight per day is most desirably employed in order toachieve effective results.

The following examples illustrate further this invention. Temperaturesare given in degrees Celsius. Solution percentages or ratios express avolume to volume relationship, unless stated otherwise. Nuclear magneticresonance spectra were recorded on a Bruker 200 MHz or 400 MHzspectrometer (a 400 MHz spectrum being noted as such in the preamble ofthe spectrum); the chemical shifts (δ) are reported in parts permillion. The concentrations for the optical rotations are express ingrams of the compound per 100 mL of solution. Abbreviations or symbolsused in the examples include Boc: t-butyloxycarbonyl; BOP.PF₆ :(benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate; Bzl: benzyl; CH₂ Cl₂, methylenedichloride; DMAP:4-(dimethylamino)pyridine; DIPEA: diisopropylethylamine; DMF:dimethylformamide; EtOH: ethanol; EtOAc: ethyl acetate; Et₂ O: diethylether; FAB/MS: fast atom bombardment mass spectrometry; HOBt:1-hydroxybenzotriazole; MeOH: methanol; Ph: phenyl; TFA: trifluoroaceticacid; THF: tetrahydrofuran.

EXAMPLE 1

Typical Preparations of Amines of Formula A--H.

(a) (S) -N,N-Dimethyl-2-[(1-phenylethyl)amino]acetamide: A mixture of2-bromo-N,N-dimethylacetamide (5.71 g, 34.4 mmol),(S)-1-phenylethylamine (4.16 g, 34.4 mmol) and triethylamine (6.96 g,68.8 mmol) in MeOH (69 mL) was stirred at room temperature (20°-22°) for30 min and then heated at reflux for 30 min. The mixture wasconcentrated under reduced pressure. The residue was dissolved in EtOAc(400 mL). The solution was washed serially with a saturated aqueoussolution of NaHCO₃ and brine, dried (MgSO₄) and concentrated to drynessunder reduced pressure. The residue was purified by flash chromatography(SiO₂, eluent: CHCl₃ -EtOH, 15:1) to give(S)-N,N-dimethyl-2-[(1-phenylethyl)amino]acetamide as a colorless oil(4.58 g, 64%); ¹ H NMR(CDCl₃) δ7.36-7.17 (m,5H), 3.76 (q, J=7.1 Hz,1H),3.24 (s,2H), 2.93 (s,3H), 2.80 (s,3H), 2.54 (broad s,1H), 1.39 (d, J=7.1Hz,3H).

By following the procedure of section (a) of this example but replacing(S)-1-phenylethylamine with an equivalent amount of(S)-2-phenylpropylamine [described by H. Biere et al., J. Med. Chem.,17, 716 (1974)], (S)-N,N-dimethyl-2-[(2-phenylpropyl)amino]acetamide [¹H NMR(CDCl₃) δ7.39-7.14 (m,5H), 3.37 (q_(AB), Δν=12 Hz, J=14.3 Hz,2H),3.07-2.68 (m,3H), 2.94 (s,3H), 2.90 (s,3H), 2.26 (broad s, 1H), 1.30 (d,J=6.5 Hz, 1H)] was obtained.

By following the procedure of section (a) of this example but replacing(S)-1-phenylethylamine with an equivalent amount of 2-phenylethylamine,N,N-dimethyl-2-[(2-phenylethyl)amino]acetamide [¹ H NMR(CDCl₃)δ7.37-7.14 (m,5H), 3.43 (s,2H), 2.96 (s,3H), 2.94 (s,3H), 2.91-2.82(m,4H), 2.06 (broad s,1H)] was obtained.

By following the procedure of section (a) of this example but replacing(S)-1-phenylethylamine with an equivalent amount of(cyclohexylmethyl)amine,2-[(cyclohexylmethyl)amino]-N,N-dimethylacetamide [¹ H NMR(CDCl₃) δ3.41(s,2H), 2.97 (s,3H), 2.96 (s,3H), 2.44 (d, J=7.1 Hz,2H), 2.21 (broads,1H), 1.86-0.82 (m, 1H)] was obtained.

By following the procedure of section (a) of this example but replacing(S)-1-phenylethylamine with twice the equivalent amount of(cyclohexylmethyl)amine and replacing 2-bromo-N,N-dimethylacetamide withan equivalent amount of 4-(2-bromo-1-oxoethyl)morpholine,4-{2-[(cyclohexylmethyl)amino]-1-oxoethyl}morpholine [¹ H NMR(CDCl₃)δ3.76-3.54 (m,3H), 3.43-3.33 (m,4H), 2.45 (d, J=6.6 Hz,2H), 2.41 (broads,1H), 1.84-0.84 (m,11H)] was obtained.

By following the procedure of section (a) of this example but replacing(S)-1-phenylethylamine with twice the equivalent amount of1-(naphthylmethyl)amine and omitting the triethylamine,N,N-dimethyl-2-[(1-naphthylmethyl)amino]acetamide [¹ H NMR(CDCl₃) δ8.25(dd, J=1.2 Hz,8.0 Hz,1H), 7.86 (dd, J=1.8 Hz,7.6 Hz,1H), 7.79 (broad d,J=8.1 Hz,1H), 7.60-7.39 (m,4H), 4.30 (s,2H), 3.52 (s,2H), 2.97 (s,3H),2.90 (s,3H)] was obtained.

(b) N-[2-(methylamino)ethyl]-N-methylmorpholinocarboxamide: To asolution of N-(tert-butyloxycarbonyl)-N,N'-dimethyl-1,2-ethanediamine(2.8 g, 14.9 mmol) in 50 mL of acetonitrile, DIPEA (3.6 mL, 20.7 mmol)and morpholinocarbonyl chloride (1.75 mL, 15.0 mmol) were added. Thereaction mixture was stirred at room temperature for 1 h. Thereafter,EtOAc and a saturated aqueous solution of NaHCO₃ were added to themixture. The organic layer was separated, washed with saturated aqueousbrine, dried (MgSO₄) and concentrated to dryness under reduced pressure.The residue was purified by flash chromatography (SiO₂, eluent:EtOAc/hexane, 3:7) to give the corresponding Boc derivative of thedesired amine as a white solid (3.18 g, 71%); 1H NMR (CDCl₃) δ3.68 (t,J=4.3 Hz, 4H), 3.39 (broad s, 4H), 3.20 (broad t, J=4.1 Hz, 4H), 2.93(s,3H), 2.86 (s,3H), 1.45 (s,9H); FAB mass spectrum, m/z: 302 (M+H)⁺,324 (M+Na)⁺.

The latter compound was deprotected as follows: A solution of the lattercompound (1.0 g, 3.3 mmol) in 4N HCl/dioxane (40 mL) was stirred at roomtemperature for 45 min. The mixture was concentrated to dryness. Theresidue was serially dissolved and the resulting solution concentrated,first with Et₂ O and then with toluene to affordN-[2-(methylamino)ethyl]-N-methylmorpholinocarboxamide as ahydrochloride addition salt (0.79 g). This amine hydrochloride salt wasused for ensuing reactions without further purification.

(c) 4-[3-(methylamino)-1-oxopropyl]morpholine: A solution of4-acryloylmorpholine (3.0 g, 21.25 mmol) in 4 mL of methylamine (40%solution in H₂ O, 57.1 mmol) was heated at 40° for 4 days. Subsequently,the reaction mixture was concentrated to dryness and the residue wasdissolved in CH₂ Cl₂ (10 mL). Triethylamine (3.7 mL, 26.5 mmol) anddi-tert-butyl dicarbonate (4.6g, 21.10 mmol) were added to the solution.The reaction mixture was stirred at room temperature for 18 h.Thereafter, EtOAc and saturated aqueous NaHCO₃ were added to themixture. The organic phase was separated, washed with saturated brine,dired (MgSO₄) and concentrated to dryness. The residue was purified byflash chromatography (SiO₂, eluent: MeOH/CHCl₃, 1:40) to give thecorresponding Boc derivative of the desired amine as a colourless oil(1.88 g, 32.5%); ¹ H NMR (CDCl₃) δ (t, J=4.6 Hz, 4H), 3.59 (broaddoublet, J=4.7 Hz, 2H), 3.49 (t, J=7.2 Hz, 4H), 2.87 (s,3H), 2.56(m,2H), 1.44 (s,9H); FAB mass spectrum, m/z: 273 (M+H)⁺, 295 (M+Na)⁺.

The latter compound (0.743 g) was deprotected in the same manner asdescribed in preceding section (b) to give4-[3-(methylamino)-1-oxopropyl]morpholine as a hydrochloride additionsalt (0.447 g). This amine hydrochloride was used for ensuing reactionswithout further purification.

(d) 4-[2-(Methylamino)ethyl]morpholine: Under a N₂ atmosphere, NaH (1.0g, 42.9 mmol, 97% dry powder) was added portionwise to a cooled solution(0°) of 4-(2-aminoethyl)morpholine (5.0 mL, 38.1 mmol) in dry THF (80mL). The resulting mixture was treating with di-tert-butyl dicarbonate(8.4 g, 38.5 mmol) and stirred for 1 h. The NaH remaining in the mixturewas decomposed by cautious dropwise addition of H₂ O. After diluting themixture with EtOAc and H₂ O, the organic layer was separated, washedwith brine, dried (MgSO₄), and concentrated under reduced pressure togive the corresponding Boc derivative of the starting material as a paleyellow oil (7.6 g, 88%); ¹ H NMR ((CDCl₃) 4.98 (broad s, 1H), 3.71 (t,J=4.6 Hz, 4H), 2.92 (m,2H), 2.46 (m,6H), 1.46 (s,9H); FAB mass spectrum,m/z: 231 (M+H)⁺.

The latter oil (5.76 g, 25 mmol) was dissolved in dry THF (60 mL). Undera N₂ atmosphere at 0°, potassium bis(trimethylsilyl)amide (40 mL of0.69M solution in THF 27.6 mmol) was added to the solution. The mixturewas stirred for 30 min. at room temperature. After an addition of methyliodide (3 mL, 49 mmol), the reaction mixture was stirred for 1 h more.The reaction mixture was diluted with H₂ O and EtOAc. The organic layerwas separated, washed with brine, dried (MgSO₄) and concentrated underreduced pressure. Purification of the residue by flash chromatography(SiO₂, eluent: MeOH/CHCl₃, 1:40) gave the corresponding Boc derivativeof the desired amine as a colourless oil (4.21 g, 69%); ¹ H NMR (CDCl₃)δ3.69 (t, J=4.5 Hz, 4H), 3.34 (m,2H), 2.87 (s,3H), 2.48 (m,6H), 1.46(s,9H); FAB mass spectrum, m/z: 245 (M+H)⁺, 267 (M+Na)⁺.

The latter compound (0.5 g) was deprotected in the same manner asdescribed in preceding section (b) to give4-[2-(methylamino)ethyl)morpholine as a hydrochloric acid addition salt.The amine hydrochloride was used for ensuing reactions without furtherpurification.

(e)(S)-N-Methyl-2-[(1-phenylethyl)amino]-N-[2-(2-pyridinyl)ethyl]acetamide:A mixture of benzyl 2-bromoacetate (30.00 g, 0.131 mol),(S)-1-phenylethyl-amine (16.18 g, 0.134 mol) and triethylamine (26.50 g,0.262 mol) in THF (300 mL) was stirred at room temperature for 6 h. H₂ O(100 mL) was added and the THF removed under reduced pressure. EtOAc(600 mL) and a saturated aqueous solution of NaHCO₃ (200 mL) were addedto the concentrate. The organic phase was washed serially with H₂ O andbrine, dried (MgSO₄) and concentrated under reduced pressure to give acolorless oil (31.42 g), i.e. the crude amino ester(Ph--(S)--CH(CH₃)--NHCH₂ C(O)OBzl). The latter compound (31.00 g) wasdissolved in CH₂ CH₂ (300 mL). Di-tert-butyl dicarbonate (25.89 g, 0.119mol) was added to the latter solution. The mixture was stirred at roomtemperature for 4 days; an additional amount of di-tert-butyldicarbonate (3.0 g) being added to the mixture on the second day.Thereafter, the mixture was washed serially with 1N aqueous HCl (2×), H₂O (2×), a saturated aqueous solution of NaHCO₃ (2×) and brine, dried(MgSO₄) and concentrated under reduced pressure to give a colorless oil(48.00 g). The latter oil was dissolved in MeOH (575 mL) and 2N aqueousNaOH (172.8 mL, 0.346 mol) was added to the solution. The mixture wasstirred at room temperature for 8 h. The mixture was concentrated underreduced pressure. The aqueous residual solution was diluted with H₂ Oand washed with CH₂ Cl₂. The aqueous phase was rendered acidic byaddition of solid citric acid (79.5 g) and then extracted with EtOAc(2×). The organic phase was washed with brine, dried (MgSO₄) andconcentrated under reduced pressure to give(S)--Ph--CH(CH₃)--N(Boc)--CH₂ C(O)OH as a colorless oil (26.85 g, 73%).

To a solution of the latter acid (4.30 g, 15.40 mmol),N-methyl-2-(2-pyridinyl)ethanamine (2.09 g, 15.40 mmol) and DIPEA (8.05mL, 46.20 mmol) in CH₂ Cl₂ (45 mL), BOP.PF₆ (6.94 g, 15.70 mmol) wasadded. The reaction mixture was stirred at room temperature for 1.5 h.EtOAc was added. The resulting solution was washed serially with asaturated aqueous solution of NaHCO₃ (2×), H₂ O (2×) and brine, dried(MgSO₄) and concentrated under reduced pressure. The residue waspurified by flash chromatography (SiO₂, eluent: EtOAc-MeOH, 30:1) togive the Boc derivative of the desired compound as a light yellow solid(4.30 g, 70%).

A solution of the latter compound (14.60 g, 36.75 mmol) in dioxane-MeOH(40 mL/3 mL) and 4N HCl/dioxane (138 mL) was stirred at room temperaturefor 1 h. The reaction mixture was diluted with EtOAc (500 mL) and anaqueous solution of 22% w/w Na₂ CO₃ (320 g) was slowly added. Theorganic phase was separated, washed with brine, dried (MgSO₄) andconcentrated under reduced pressure to give(S)-N-methyl-2-[(1-phenylethyl)amino]-N-[2-(2-Pyridinyl)ethyl]acetamideas a pale yellow oil (10.50 g, 96%); ¹ H NMR(CDCl₃) δ (1.2:1.0 mixtureof rotamers) 8.51, 8.40 (2 broad d, J˜4.6, 4.6 Hz, 1H), 7.59, 7.53 (2td, J=7.6, 1.9 and 7.6, 1.9 Hz, 1H), 7.34-7.22 (m,5H), 7.18, 6.96 (2d,J=7.6, 7.6 Hz, 1H), 7.14-7.06 (m, 1H), 3.82 (q, J=6.7 Hz, 0.5H),3.77-3.67 (m,1.5H), 3.52 (t, J=7.3 Hz, 1H), 3.25, 3.17 (s, ABq, Δν=18.5Hz, J=15.5 Hz, 2H), 3.22 (broad s, 1H), 2.99 (t, J=7.3 Hz, 1H), 2.91,2.72 (2s,3H), 2.90-2.85 (m, 1H), 1.41, 1.36 (2d, J=6.7, 6.7 Hz, 3H). Thelatter amine was used for ensuing reactions without furtherpurification.

The procedure of section (e) can be used generally to prepare many ofthe amines of formula A--H. For example, by following the latterprocedure but replacing (S)-1-phenylethylamine with an equivalent amountof benzylamine,N-methyl-2-[(phenylmethyl)amino]-N-[2-(2-pyridinyl)ethyl]acetamide wasobtained via the corresponding Boc derivative. The Boc derivative hadthe following NMR: ¹ H NMR (CDCl₃) δ8.60 (d, J=5 Hz, 1H), 8.40 (m, 1H),7.70-7.00 (m,7H), 4.55-4.52 and 4.48 (2s,2H), 3.90 (d, J=11 Hz, 1H),3.80-3.55 (m,2H), 3.10-2.90 (m,3H), 2.90 (s,3H), 1.50 (3s,9H).

EXAMPLE 2 Preparation of N⁴ -[2-(Dimethylamino)-2-oxoethyl]-N⁴-[1(S)-phenylethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide

(a) 4-Bromo-4-pentenoic acid: tert-Butyl acetate (35 g, 301 mmol) wasadded dropwise to a stirred, freshly prepared solution of lithiumdiisopropylamine (319 mmol) in THF (800 mL) at -78°. The mixture wasstirred for 25 min at -78°. Thereafter, 2,3-dibromo-1-propene (88.6 g,443 mmol) was added to the mixture. Stirring was continued at -78° foran additional 4 h. The mixture was quenched at -78° with a saturatedaqueous solution of NH₄ Cl. The THF was removed under reduced pressure.The oily residue was dissolved in EtOAc. The organic layer was washedwith a saturated aqueous solution of NH4Cl (1×), H₂ O (1×) and brine(2×), dried (MgSO₄) and concentrated. The residue was dissolved in asolution of TFA-CH₂ Cl₂ (1:1, 500 mL) and the resulting solution wasallowed to stand at room temperature for 1 h. The volatiles were removedby evaporation under reduced pressure. The residue was taken up in asaturated aqueous solution of NaHCO₃. The resulting solution was washedtwice with CH₂ Cl₂. The aqueous phase was rendered acidic with 1Naqueous HCl and extracted with EtOAc (2×). The EtOAc extract was washedwith brine (1×), dried (MgSO₄) and evaporated to dryness to give4-bromo-4-pentenoic acid (39.7 g, 74%); ¹ H NMR ((CDCl₃) δ11.45 (broads,1H), 6.13 (d, J=2.9 Hz,1H), 5.93 (d, J=2.9 Hz,1H), 3.40-3.05 (m,4H).

(b) 3-(4-Bromo-1-oxo-4-pentenyl)-4(S)-(1-methylethyl)-2-oxazolidinone: Asolution of mixed anhydride was prepared by adding, under N₂, pivaloylchloride (253 μL, 2.06 mmol) to a stirred solution of4-bromo-4-pentenoic acid (350 mg, 1.96 mmol) and triethylamine (332 μL,2.38 mmol) in dry THF (3.3 mL) cooled to -78°. The mixture was warmed to0°, stirred for 1 h and then cooled to -78°. Another solution wasprepared by adding dropwise under N₂ a 1.6M hexane solution ofbutyllithium (1.1 mL, 1.79 mmol) to a cooled solution (-45° to -50°) of(S)-4-(1-methylethyl)-2-oxazolidinone [230 mg, 1.79 mmol, described byL. N. Pridgen et al., J. Org. Chem., 54, 3231 (1989)] in dry THF (8.9mL). The latter solution was cooled to -78° and then added rapidly, viacannulation, to the stirred solution of the mixed anhydride, notedpreviously. The resulting mixture was stirred at -78° for 2 h. Afterwarming to 0°, the mixture was partitioned between CH₂ Cl₂ and phosphatebuffer (pH 7). The CH₂ C₂ layer was separated, washed with a saturatedaqueous solution of NaHCO₃ (1×) and brine (1×), dried (MgSO₄) andevaporated to dryness under reduced pressure. The residual oil waspurified by flash chromatography (SiO₂, eluent: EtOAc-hexane, 1:9) togive the desired 2-oxazolidinone derivative as a colorless oil (354 mg,69%); ¹ H NMR ((CDCl₃) δ5.67 (d, J=2.9 Hz,1H), 5.54 (d, J=2.9 Hz,1H),4.50-4.35 (m,1H), 4.35-4.15 (m,2H), 3.35-3.05 (m,2H), 2.90-2.70 (m,2H),2.50 (hept d, J=3.8 Hz,8.6 Hz,1H), 0.93 (d, J=8.6 Hz,3H), 0.87 (d, J=8.6Hz,3H).

(c) 3-(5-Bromo-1,4-dioxopentyl)-4(S)-(1-methylethyl)-2-oxazolidinone:Recrystallized N-bromosuccinimide (960 mg, 5.39 mmol) was added to acold (0°) stirred solution of the 2-oxazolidinone derivative of section(b) of this example (311.6 mg, 1.08 mmol) in acetonitrile (10 mL) and H₂O (485 μL, 27.0 mmol). The resulting orange mixture was stirred at 0°for 30 min and then allowed to warm to room temperature. After 1 h thereaction mixture was quenched with a 10% (w/v) aqueous solution of Na₂S₂ O₃, and extracted with EtOAc. The EtOAc extract was washed seriallywith H₂ O, 10% (w/v) aqueous Na₂ S₂ O₃, H₂ O and brine. Drying (MgSO₄)and concentration of the extract afforded a yellow oil. The oil waspurified by flash chromatography (SiO₂, eluent: EtOAc-hexane, 3:7) togive the bromoketone,3-(5-bromo-1,4-dioxopentyl)-4(S)-(1-methylethyl)-2-oxazolidinone, as acolorless oil (320 mg, 97%); ¹ H NMR (CDCl₃) δ4.50-4.35 (m,1H),4.35-4.15 (m,2H), 4.01 (s,2H), 3.35-3.20 (m,2H), 3.05-2.90 (m,2H), 2.33(hept d, J=3.7 Hz,7.0 Hz,1H), 0.91 (d, J=7.0 Hz,3H), 0.87 (d, J=7.0Hz,3H).

(d)3-[3-(2-Amino-4-thiazolyl)-1-oxopropyl]-4(S)-(1-methylethyl)-2-oxazolidinone:Thiourea (3.12 mg, 4.10 mmol) was added to a solution of the bromoketoneof section (c) of this example (250 mg, 0.82 mmol) in isopropanol (8.2mL). The mixture was stirred at 50° for 20 min, cooled and evaporated todryness under reduced pressure. The residue was dissolved in EtOAc. TheEtOAc solution was washed with an saturated aqueous solution of NaHCO₃(2×), H₂ O (2×) and brine (1×), dried (MgSO₄) and evaporated to drynessto give the desired aminothiazolyl derivative as a solid (197 mg, 85%);¹ H NMR (CDCl₃) δ6.16 (s,1H), 5.37 (broad s,2H), 4.55-4.35 (m,1H),4.35-4.15 (m,2H), 3.45-3.10 (m,2H), 3.05-2.80 (m,2H), 2.35 (hept d,J=3.8 Hz,7.0 Hz,1H), 0.90 (d, J=7.0 Hz,3H), 0.85 (d, J=7.0 Hz,3H). Theproduct was used for the next step without further purification.

(e)4(S)-(1-Methylethyl)-3-{3-{2-[(2,2,2-trichloroethoxy)carbonylamino]-4-thiazolyl}-1-oxopropyl}-2-oxazolidinone:2,2,2-Trichloroethyl chloroformate (171 μL, 1.24 mmol) was added to asolution of the aminothiazolyl derivative of section (d) of this example(185 mg, 0.65 mmol), DIPEA (205 μL, 1.18 mmol) and DMAP (8 mg, 0.07mmol) in CH₂ Cl₂ (3.3 mL) at room temperature. The reaction mixture wasstirred at room temperature for 1 h. Thereafter, the mixture was dilutedwith EtOAc, washed serially with a saturated aqueous solution of NaHCO₃(2×), H₂ O (3×) and brine (2×), dried (MgSO₄) and evaporated to dryness.The residue was purified by flash chromatography (SiO₂, eluent:EtOAc-hexane, 3:7) to give the desired product (250 mg, 84%); ¹ H NMR(400 MHz, (CDCl₃) δ10.27 (broad s,1H), 6.64 (s,1H), 4.93 (q_(AB) J_(AB)=12.0 Hz,2H), 4.48-4.38 (m,1H), 4.32-4.18 (m,2H), 3.45-3.20 (m,2H),3.20-3.05 (m,2H), 2.36 (hept d, J=3.8 Hz,7.0 Hz,1H), 0.91 (d, J=7.0Hz,3H), 0.86 (d, J=7.0 Hz,3H); FAB mass spectrum, m/z: 458 (M+H)⁺, 480(M+Na)⁺.

(f)3-{4-tert-Butoxy-4-oxo-2(R)-{{2-[(2,2,2-trichloroethoxy)carbonylamino]-4-thiazolyl}methyl}butyl}-4(S)-(1-methylethyl)-2-oxazolidinone:A solution of the product of section (e) of this example (615 mg, 1.35mmol) in THF (5.0 mL) was added to a cold (-78°) solution of sodiumbis(trimethylsilyl)amide (3.1 mL, 3.1 mmol) in THF (3.0 mL). [Sodiumbis(trimethylsilyl)amide is supplied as a 1M solution in THF by theAldrich Chemical Co., Inc., Milwaukee, Wis., U.S.A.] The mixture wasstirred at -78° for 40 min. A solution of tert-butyl 2-bromoacetate (435μL, 2.69 mmol) in THF (1 mL) was added to the mixture which was thenstirred at -78° for 1.5 h. The mixture was quenched with a saturatedaqueous solution of NH₄ Cl and diluted with EtOAc. The organic phase wasseparated, washed with H₂ O and brine, dried (MgSO₄) and evaporated. Theresidue was purified by flash chromatography (SiO₂ O, eluent:EtOAc-hexane, 1:4) to give the desired tert-butyl ester derivative (459mg, 60%); ¹ H NMR (400 MHz, (CDCl₃) δ10,.50 (broad s,1H), 6.70 (s,1H),4.92 (q_(AB), J_(AB) =12.1 Hz,2H), 4.55-4.40 (m,1H), 4.40-4.30 (m,1H),4.20-4.05 (m,2H), 3.10-2.90 (m,2H), 2.85-2.65 (m,1H), 2.47-2.38 (m,1H),2.32 (hept d, J=3.8 Hz,7.0 Hz,1H), 1.39 (s,9H), 0.89 (d, J=7.0 Hz,3H),0.87 (d, J=7.0 Hz,3H); FAB mass spectrum, m/z: 572 (M+H)⁺.

(g) The protected amido acid,4-{[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]amino}-4-oxo-3(R)-{{2-[(2,2,2-trichloroethoxy)carbonylamino]-4-thiazolyl}methyl}butanoicacid tert-butyl ester: A solution of the product of section (f) of thisexample (57.5 mg, 0.10 mmol) in THF (1.5 mL) and H₂ O (0.5 mL) wascooled to 0°. A 30% aqueous solution of H₂ O₂ (91.3 μL, 0.80 mmol of H₂O₂) and lithium hydroxide monohydrate (8.5 mg, 0.20 mmol) were addedserially to the cooled solution. The mixture was stirred at 0° for 5 minand then at room temperature for 2.5 h. Excess H₂ O₂ was quenched by theaddition of a 1.5M aqueous solution of Na₂ SO₃ (as judged by a KI stickindicator). The resulting mixture was diluted with H₂ O and washed withCH₂ Cl₂ (3×). The aqueous layer was rendered acidic with 1N aqueous HCland extracted with EtOAc (3×). The combined EtOAc extracts were washedwith brine, dried (MgSO₄) and concentrated to dryness to yield thedesired monoprotected dicarboxylic acid, i.e. the 4-tert-butyl ester of2(R)-{{2-[(2,2,2-trichloroethoxy)carbonylamino]-4-thiazolyl}-methyl}butanedioicacid. The monoprotected dicarboxylic acid was used for the followingcoupling step without purification.

The monoprotected dicarboxylic acid (0.10 mmol) was dissolved in DMF (1mL). DIPEA (43.8 μL, 0.25 mmol), BOP.PF₆ (48 mg, 0.11 mmol) and2(S)-amino-1-cyclohexyl-6-methyl-3(R),4(S)-heptanediol hydrochloride (30mg, 0.11 mmol) were added to the solution. The pH of the mixture wasadjusted to pH 8.5 with DIPEA. The resulting mixture was stirred at roomtemperature for 2.5 h. Thereafter, the mixture was diluted with EtOAc.The organic phase was washed with 1N HCl, a saturated aqueous solutionof NaHCO₃, H₂ O and brine, dried (MgSO₄) and evaporated to dryness. Theresidue was purified by flash chromatography (SiO₂, eluent:EtOAc-hexane, 3:7) to give desired protected amide (27.9 mg, 40%); ¹ HNMR (400 MHz, (CDCl₃) δ10.23 (broad s, 1H), 6.66-6.59 (m,2H), 4.85(q_(AB), J_(AB) =11.8 Hz,2H), 4.55-4.40 (m,1H), 4.30-4.15 (m,1H),3.55-3.43 (m,1H), 3.35-3.05 (m,3H), 3.05-2.85 (m,1H), 2.80-2.65 (m,1H),2.43-2.33 (m,1H), 2.00-1.80 (m,1H), 1.80-1.70 (m,1H), 1.70-1.00 (m,11H),1.44 (s,9H), 1.00-0.70 (m,3H), 0.94 (d, J=6.6 Hz,3H), 0.85 (d, J=6.6Hz,3H).

(h) The title compound: The preceding protected amido acid (190 mg, 0.28mmol) was dissolved in a solution of TFA-CH₂ Cl₂ (1:1, 5 mL) and theresulting solution was allowed to stand at room temperature for 1 h. Thesolution was evaporated to dryness. The residue was dissolved in DMF (2mL). DIPEA (97 μL, 055 mmol), BOP•PF₆ (159 mg, 0.36 mmol) and(S)-N,N-dimethyl-2-[(1-phenylethyl)amino]acetamide [74 mg, 0.36 mmol,described in example 1, section (a)] were added serially to the DMFsolution. The pH of the solution was adjusted to 8.5 with DIPEA.Thereafter, the reaction mixture was stirred at room temperature for 18h. The mixture was diluted with EtOAc. The organic phase was washed with1N aqueous HCl (1×), a saturated aqueous solution of NaHCO₃ (2×), brine(2×), dried (MgSO₄) and concentrated to dryness. The residue waspurified by flash chromatography (SiO₂, eluent: hexane-EtOAc-MeOH,100:97:3) to give the correspondingN-{2-[(2,2,2-trichloroethoxy)carbonyl]} derivative of the title compoundas a yellow oil (84 mg, 37%); ¹ H NMR (400 MHz, CDCl₃) (ca 1.5:1-mixtureof isomers) δ9.80 (s,1H), 7.40-7.20 (m,5H), 6.84 and 6.75 (2d, J=8.8Hz,8.8 Hz,1H), 6.78 and 6.63 (2s,1H), 6.10 and 5.15 (2q, J=6.9 Hz,6.9Hz,1H), 4.85 (q_(AB), J_(AB) =11.9 Hz,2H), 4.46-4.18 (m,2H), 3.85-3.05(m,5H), 3.05-2.40 (m,4H), 2.92, 2.87, 2.91 and 2.80 (4s,6H), 2.00-1.80(m,1H), 1.80-1.05 (m,14H), 1.56 and 1.40 (2d,6.9 Hz,6.9 Hz,3H),1.05-0.75 (m,2H), 0.93 (d, J=6.6 Hz,3H), 0.84 (d, J=6.6 Hz,3H); FAB massspectrum, m/z: 820 (M+H)⁺, 644 (M-C₂ H₂ O₂ Cl₃)⁺ ; [α]_(D) ²⁵ -45.6° (c1.00, MeOH). The (2,2,2-trichloroethoxy)carbonyl protective group of thelatter derivative was eliminated as follows: The latter derivative (645mg, 0.79 mmol) was dissolved in 1N aqueous HCl/dioxane (1:2, 6 mL). Zincmetal powder (6.45 g) was added to the solution. The mixture wassonicated at room temperature for 4.5 h. A saturated aqueous solution ofNaHCO₃ was added. The suspended zinc salt was collected on a filter andwashed several times with EtOAc. The organic phase in the filtrate wasseparated and washed with a saturated aqueous solution of NaHCO₃ (2×),brine (2×), dried (MgSO₄) and evaporated to dryness. The residue waspurified by flash chromatography (SiO₂, eluent: MeOH-EtOAc, 3:97) togive the title compound as a white solid (438 mg, 86%); ¹ H NMR (400MHz, CDCl₃) (ca 1.5:1 mixture of rotamers) δ7.38-7.22 (m,5H), 6.77 and6.64 (2d, J=8.5 Hz,8.5 Hz,1H), 6.27 and 6.23 (2s,1H), 6.05 and 5.18 (q,J=6.6 Hz,6.6 Hz,1H), 5.40-5.25 (m,2H), 4.65-4.45 (m,1H), 4.4 5-4.18(m,1H), 3.85-3.70 (m,1H), 3.70-3.40 (m,1H), 3.40-3.10 (m,3H), 3.10-2.50(m,5H), 2.94, 2.88, 2.91 and 2.83 (4s,6H), 2.00-1.85 (m,1H), 1.85-1.73(m,1H), 1.59 and 1.38 (2d, J=6.8 Hz,6.8 Hz,3H,rotamers), 1.73-1.05(m,12H), 0.93 (d, J=6.7 Hz,3H), 0.85 (d, J=6.7 Hz,3H), 1.00-0.75 (m,2H);FAB mass spectrum, m/z: 644 (M+H)⁺, 628 (M-Me)⁺ ; [α]_(D) ²⁵ -58.8° (c1.00, MeOH).

Alternatively, the title compound was prepared as follows:

3-{4-tert-Butoxy-4-oxo-2(R)-{{2-[(2,2,2-trichloroethoxy)carbonylamino]-4-thiazolyl}methyl}butyl}-4(S)-(1-methylethyl)-2-oxazolidinone(5.78 g, 10.1 mmol), i.e. the product of section (f) of this example),was dissolved in a solution of TFA-CH₂ Cl₂ (1:1, 50 mL). The solutionwas stirred at 0° for 1 h and then at room temperature for 2.5 h.Thereafter, the solution was evaporated to dryness. The residue wasdissolved in DMF (51 mL). DIPEA (2.1 mL, 12.2 mmol), BOP•PF₆ (5.37 g,12.2 mmol) and (S)-N,N-dimethyl-2-[(1-phenylethyl)amino]acetamide (2.40g, 11.6 mmol) were added serially to the DMF solution at 0°. The pH ofthe solution was adjusted to 8.5 with DIPEA. The reaction mixutre wasstirred at 0° for 30 min and then at room temperature for 3.5 h. Themixture was diluted with EtOAc. The organic phase was washed with 1Naqueous HCl (1×), a saturated aqueous solution of NaHCO₃ (2×), brine(2×), dried (MgSO₄) and concentrated to dryness. The residue waspurified by flash chromatography (SiO₂, eluent: hexane--CHCl₃ -MeOH,5.5:3.5:1) to give the desired chiral acyloxazolidinone synthon of4-{[2-(dimethylamino)-2-oxoethyl)]-[1(S)-phenylethyl]amino}-4-oxo-2(R)-{{2-[(2,2,2-trichloroethoxy)carbonylamino]-4-thiazolyl}methyl}butanoicacid (4.84 g, 68%).

The chiral acyloxazolidinone synthon was transformed to the desiredsynthon as follows: A solution of the chiral acyloxazolidinone synthon(4.22 g, 6.0 mmol) in THF (90 mL) and H₂ O (30 mL) was cooled to 0°. A30% aqueous solution of H₂ O₂ (4.9 mL, 48.0 mmol of H₂ O₂) and lithiumhydroxide monohydrate (504 mg, 12.0 mmol) were added serially to thecooled solution. The mixture was stirred at 0° for 30 min and then atroom temperature for 2.5 h. Excess H₂ O₂ was quenched by the addition ofsolid Na₂ SO₃. The resulting mixture was diluted with water and renderedacidic with 1N aqueous HCl and extracted with EtOAc (3×). The combinedEtOAc extracts were washed with 1N aqueous HCl (1×), brine (2×), dried(MgSO₄) and concentrated to dryness to yield the desired amido acid,i.e.4-{[2-(dimethylamino)-2-oxoethyl)]-[1(S)-phenylethyl]amino}-4-oxo-2(R)-{{2-[(2,2,2-trichloroethoxy)carbonylamino]-4-thiazolyl}methyl}butanoicacid. The amido acid was used for the following coupling step withoutpurification.

The preceding amido acid (6.0 mmol) was dissolved in DMF (48 mL). DIPEA(1.6 mL, 9.0 mmol) and BOP•PF₆ (3.2 g, 7.2 mmol) were added to thesolution. The resulting mixture was stirred at 0° for 30 min.Thereafter, 2(S)-amino-1-cyclohexyl-6-methyl-3(R),4(S)-heptanediolhydrochloride (2.0 g, 7.2 mmol) was added to the cooled solution. The pHof the solution was adjusted to 8.5 with DIPEA. The mixture was allowedto warm to room temperature over a period of 4.5 h. The mixture wasdiluted with EtOAc (1 L). The organic phase was washed with 1N aqueousHCl (1×), a saturated aqueous solution of NaHCO₃ (2×), brine (2×), dried(MgSO₄) and evaporated to dryness. The residue was purified by flashchromatography (SiO₂, eluent: EtOAc-hexane-EtOH, 6:3:1) to give, aftertrituration with hexane/Et₂ O (1:1), theN-{2-[(2,2,2-trichloroethoxy)carbonyl]} derivative of the title compoundof this example (3.2 g, 65%), identical to the corresponding derivativeof section (h) of this example. The (2,2,2-trichloroethoxy)carbonylprotective group of the latter derivative was removed in the same manneras described in section (h) to give the title compound.

EXAMPLE 3 Preparation of N⁴ -[2-(Dimethylamino)-2-oxoethyl]-N⁴-[1(S)-phenylethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-(1H-imidazol-4-ylmethyl)butanediamide

(a) 1-(Triphenylmethyl)-1H-imidazole-4-propanoic acid: Triethylamine(26.73 g, 36.8 mL, 0.26 mol) was added dropwise to a solution of1H-imidazole-4-propanoic acid methyl ester [32.58 g, 0.21 mol, describedby J. Altman et al., J. Chem. Soc., Perkin Trans. 1, 59 (1984)] andtriphenylmethyl chloride (64.80 g, 0.23 mol) in CH₂ Cl₂ at roomtemperature. The mixture was stirred at room temperature for 63 h,diluted with CH₂ Cl₂ (total volume=900 mL), washed with H₂ O (2×), asaturated aqueous solution of NaHCO₃ (1×) and brine (1×), dried (MgSO₄)and concentrated to dryness under reduced pressure. The residue wasdissolved in a mixture of THF/H₂ O (630 mL:210 mL). Lithium hydroxidemonohydrate (22.03 g, 0.52 mol) was added to the solution. The mixturewas stirred at room temperature for 3 h. Most of the THF was removed bydistillation under reduced pressure. The residue was poured into H₂ O (1L). The pH of the resulting mixture was adjusted to 2 by the addition of10% (w/v) aqueous citric acid. The mixture was extracted with CH₂ Cl₂(3×). The CH₂ Cl₂ extract was washed with 10% (w/v) aqueous citric acidand brine, dried (MgSO₄) and concentrated under reduced pressure. Theresidue was triturated with Et₂ O to give the desired acid as a whitesolid (77.14 g, 96%); ¹ H NMR (CDCl₃) δ7.67 (d, J=1.5 Hz, 1H), 7.41-7.34(m,9H), 7.13-7.08 (m,6H), 6.66 (d, J=1.5 Hz,1H), 2.95-2.88 (m,2H),2.82-2.76 (m,2H).

(b)4(S)-(1-Methylethyl)-3-{1-oxo-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]propyl}-2-oxazolidinone:By following the procedure of example 2, section (b) and using theproduct of section (a) of this example (11.5 g, 30.1 mmol) to preparethe corresponding mixed anhydride which in turn is reacted with the(S)-4-(1-methylethyl)-2-oxazolidinone (3.53 g, 27.3 mmol), the desiredproduct was obtained as a pale yellow solid (11.38 g, 84%); ¹ HNMR(CDCl₃) δ7.36-7.29 (m,10H), 7.17-7.10 (m,6H), 6.58 (d, J=0.7 Hz,1H),4.40 (td, J=3.8 Hz, 7.5 Hz,1H), 4.29-4.14 (m,2H), 3.32-3.23 (m,2H),2.96-2.88 (m,2H), 2.33 (hept d, J=3.8 Hz, 6.9 Hz, 1H), 0.89 (d, J=7.0Hz, 3H), 0.82 (d, J=6.9 Hz,3H).

(c)3-{1,4-Dioxo-4-(phenylmethoxy)-2(R)-{[1-(triphenylmethyl)-1H-imidazol-4-yl]methyl}butyl}-4(S)-(1-methylethyl)-2-oxazolidinone:By following the procedure of example 2, section (f), but replacing theproduct of section (e) of that example with4(S)-(1-methylethyl)-3-{1-oxo-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]propyl}-2-oxazolidinoneof section (b) of this example, and replacing tert-butyl 2-bromoacetatewith benzyl 2-bromoacetate,3-{1,4-dioxo-4-(phenylmethoxy)-2-{[1-(triphenylmethyl)-1H-imidazol-4-yl]methyl}butyl}-4(S)-(1-methylethyl)-2-oxazolidinonewas obtained as a mixture of 2(R)- and 2(S)-epimers in a 8 to 1 ratio byweight. Separation of the epimers by flash chromatography (SiO₂, eluent:hexane-EtOAc, 1:2) yielded the desired 2(R)-epimer (Rf=0.25, eluent:hexane-EtOAc,1:2). The ¹ H NMR(CDCl₃) of the 2(R)-epimer showedδ7.34-7.28 (m,15H), 7.13-7.08 (m,6H), 6.59 (d, J=1.3 Hz,1H), 5.06(s,2H), 4.55-4.45 (m,1H), 4.38 (td, J=3.9 Hz,5.4 Hz,1H), 4.15-4.10(m,2H), 2.97 (dd, J=10.3 Hz,16.9 Hz,1H), 2.88 (dd, J=6.3 Hz,14.3 Hz,1H),2.73 (dd, J=7.0 Hz,14.3 Hz,1H), 2.59 (dd, J=4.4 Hz,16.9 Hz,1H), 2.32(hept d, J=3.9 Hz,7.0 Hz,1H), 0.87 (d, J=7.1 Hz,3H), 0.85 (d, J=6.8Hz,3H).

(d)4-{[1(S)-(Cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]amino}-4-oxo-3(R)-{[(1-(triphenylmethyl)-1H-imidazol-4-yl]methyl}butanoicacid benzyl ester: A 30% aqueous solution of H₂ O₂ (4.70 mL, 41.6 mmol)and lithium hydroxide monohydrate (436 mg, 10.4 mmol) were addedserially to cooled solution (0°) of the product of section (c) of thisexample (6.67 g, 10.4 mmol) in THF-H₂ O (156 mL: 52 mL). The reactionmixture was stirred at 0° for 2 h and then at room temperature for 2 h.Excess peroxide was quenched at 0° with 1.5N aqueous Na₂ SO₃ solution.THF was removed by distillation under reduced pressure. The concentratewas poured into H₂ O (500 mL). The mixture was rendered acid by theaddition of a 10% (w/v) aqueous solution of citric acid, and thenextracted with EtOAc. The extract was washed with brine, dried (MgSO₄)and evaporated to dryness under reduced pressure to yield the desiredmonoprotected dicarboxylic acid, i.e. the 4-(phenylmethyl) ester of2(R)-{[1-(triphenylmethyl)-1H-imidazol-4-yl]methyl}butanedioic acid. Themonoprotected dicarboxylic acid was used for the following coupling stepwithout further purification.

2(S)-Amino-1-cyclohexyl-6-methyl-3(R),4(S)-heptanediol hydrochloride(2.91 g, 10.4 mmol), DIPEA (3.62 g, 28.0 mmol) and BOP•PF₆ (4.82 g, 10.9mmol) were added to a cooled (0°) solution of the precedingmonoprotected dicarboxylic acid in DMF (42 mL). The mixture was stirredat room temperature for 6 h. Thereafter, the mixture was diluted withEtOAc. The organic phase was washed with a 10% (w/v) aqueous solution ofcitric acid (2×), H₂ O (1×), a saturated aqueous solution of NaHCO₃ andbrine, dried (MgSO₄) and concentrated to dryness under reduced pressure.The residue was purified by flash chromatography (SiO₂, eluent:hexaneisopropanol,8:1) to give the desired protected amido acid as awhite solid (6.08 g, 77%); ¹ H NMR (CDCl₃) δ7.42 (d, J=1.2 Hz,1H),7.37-7.30 (m,14H), 7.12-7.05 (m,6H), 6.54 (d, J=1.2 Hz,1H), 6.45 (broadd, J=9.6 Hz,1H), 5.11 (d, J=12.3 Hz,1H), 5.06 (d, J=12.3 Hz,1H),4.43-4.38 (m,1H), 3.30-2.64 (m,6H), 2.37 (dd, J=4.8 Hz,15.6 Hz,1H),1.92-0.73 (m,16H), 0.87 (d, J=6.6 Hz,3H), 0.69 (d, J=6.5 Hz,3H).

(e) N¹ -[1(S)-(Cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-N⁴-[2-(dimethylamino)-2-oxoethyl]-N⁴-[1(S)-phenylethyl]-2(R)-{[1-(triphenylmethyl)1H-imidazol-4-yl]methyl}butanediamide:A mixture of the protected amido acid of section (d) of this example(6.08 g, 8.04 mmol) and 10% palladium on carbon (600 mg) in EtOH (80 mL)was stirred under one atmosphere of hydrogen for 2.5 h. The mixture wasfiltered and the filtrate was concentrated to dryness under reducedpressure to give the desired amido acid, i.e.4-{[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]amino}-3(R)-{[1-(triphenylmethyl)-1H-imidazol-4-yl]methyl}-4-oxobutanoicacid, as a white solid (5.30 g, 99%). Without further purification, thelatter amido acid was dissolved in DMF (32 mL) and cooled to 0°.(S)-N,N-dimethyl-2-[(1phenylethyl)amino]acetamide [1.66 g, 8.07 mmol,described in example 1, section (a)], DIPEA (1.42 g, 10.98 mmol) andBOP•PF₆ (3.00 g, 6.78 mmol) were added to the cooled solution. Thereaction mixture was stirred at 0° for 15 min and then at roomtemperature for 5 h. Thereafter, the mixture was diluted with EtOAc,washed successively with a 10% (w/v) aqueous solution of citric acid, H₂O, a saturated aqueous solution of NaHCO₃ and brine, dried (MgSO₄) andconcentrated to dryness under reduced pressure. The residue was purifiedby flash chromatography (SiO₂, eluent: EtOAc-MeOH, 10:1) to give thedesired product as a yellow solid (3.60 g, 65%); ¹ H NMR (CDCl₃) (ca 1:1mixture of rotamers) δ7.46 and 7.23 (2d, J=1.1 Hz,1.1 Hz,1H), 7.40-7.20(m,14H), 7.15-7.00 (m,6H), 6.84-6.69 (m,1H), 6.71 and 6.64 (2d, J=1.1Hz,1.1 Hz,1H), 6.01 and 5.19 (2q, J=6.9 Hz,6.9 Hz,1H), 4.48-4.18 (m,1H),4.33, 3.14 and 3.84 (2d and q_(AB), Δν=21.5 Hz, J=16.2 Hz,16.2 Hz,17.8Hz,2H), 3.42-2.57 (m,7H), 2.96, 2.88, 2.87 and 2.82 (4s,6H), 1.96-1.03(m,16H), 1.56 and 1.35 (2d, J=6.9 Hz,6.9 Hz,3H), 0.89, 0.88, 0.83 and0.74 (4d, J=6.6 Hz,6.7 Hz,6.5 Hz,6.5 Hz,6H).

(f) The title compound: A mixture of the product of section (e) of thisexample (3.60 g, 4.21 mmol) and 10% (w/w) palladium hydroxide on carbon(1.44 g) in EtOH (50 mL) was shaken under an hydrogen atmosphere (50psi) on a Parr hydrogenation apparatus for 2 days. The mixture wasfiltered. The filtrate was concentrated under reduced pressure. Theresidue was purified by flash chromatography (SiO₂, eluent: EtOAc-MeOH,10:1) to give the title compound as a white solid; ¹ H NMR [(CD₃)₂ SO](1.5:1.0 mixture of rotamers) δ7.72 and 7.61 (2d, J=8.4 Hz,8.8 Hz,1H),7.54 and 7.50 (2 broad s,1H), 7.41-7.21 (m,5H), 6.83 and 6.77 (2 broads,1H), 5.76 and 5.15 (2q, J=7.2 Hz,6.8 Hz,1H), 4.24, 4.12, 3.78 and 3.43(4d, J=16.1 Hz,18.0 Hz,18.0 Hz,16.1 Hz,2H), 4.08 (broad s,1H), 3.20-2.95(m,2H), 2.94-2.68 (m,2H), 2.87, 2.82, 2.77 and 2.74 (4s,6H), 2.67-2.46(m,2H), 2.34 (d, J=6.9 Hz,1H), 1.83-0.98 (m,16H), 1.45 and 1.31 (2d,J=6.8 Hz and 7.2 Hz,3H), 0.84 (d, J=6.6 Hz,3H), 0.72 (d, J=6.4 Hz,3H);FAB mass spectrum, m/z: 612 (M+H)⁺, 634 (M+Na)⁺ ; [α]_(D) ²⁵ -59.1° (c1.02, MeOH).

EXAMPLE 4 Preparation of N⁴ -[2-(Dimethylamino)-2-oxoethyl]-N⁴ -[1(S)-phenylethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-(4-thiazolylmethyl)butanediamide

(a) 4(S)-(1-Methylethyl)-3-[1-oxo-3-(4-thiazolyl)propyl-2-oxazolidinone:Thioformamide (8.52 g, 0.14 mol) was added to a stirred solution of thebromoketone of example 2, section (c) (7.12 g, 23.3 mmol) in THF (120 mL). The mixture was stirred at room temperature for 5 h. Thereafter, themixture was diluted with Et₂ O, washed with 10% (w/v) aqueous NaHCO₃ andthen H₂ O, dried (MgSO₄) and concentrated to dryness under reducedpressure to give4(S)-(1-methylethyl)-3-[1-oxo-3-(4-thiazolyl)propyl]-2-oxazolidinone(3.8 g, 61%); ¹ H NMR(CDCl₃) δ8.75 (s,1H), 7.05 (s,1H), 4.47-4.40(m,1H), 4.30-4.16 (m,2H), 3.46-3.36 (m,2H), 3.28-3.17 (m,2H), 2.45-2.28(m,1H), 0.90 (d, J=7.1 Hz,3H), 0.86 (d, J=6.9 Hz,3H).

(b)3-[4-tert-Butoxy-1,4-dioxo-2(R)-(4-thiazolylmethyl)butyl]-4(S)-(1-methylethyl)-2-oxazolidinone:The product of section (a) of this example (825 mg, 3.07 mmol) wasstereoselectively alkylated with tert-butyl 2-bromoacetate according tothe procedure described in example 2, section (f) to give a mixture ofthe desired3-[4-tert-butoxy-1,4-dioxo-2(R)-(4-thiazolylmethyl)butyl]-4(S)-(1-methylethyl)-2-oxazolidinone(Rf=0.25, eluent: EtOAc-hexane, 1:2) and its corresponding 2(S)-epimer(Rf=0.41, eluent: EtOAc-hexane, 1:2) in a 7:1 ratio, respectively. Flashchromatography (SiO₂, eluent: EtOAc-hexane, 1:2) yielded the puredesired compound as a white solid (882 mg, 75%), ¹ H NMR(CDCl₃) δ8.75(s,1H), 7.14 (s,1H), 4.62-4.5 (m,1H), 4.50-4.40 (m,1H), 4.29-4.20(m,2H), 3.19 (dd, J=6.4 Hz,14.2 Hz,1H), 3.02 (dd, J=7.5 Hz,14.2 Hz,1H),2.84 (dd, J=9.8 Hz,16.6 Hz,1H), 2.49 (dd, J=4.7 Hz,16.6 Hz,1H), 1.41(s,9H), 0.95 (d, J=6.8 Hz,3H), 0.92 (d, J=7.0 Hz,3H).

(c)4-{[1(S)-(Cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]amino}-4-oxo-3(R)-(4-thiazolylmethyl)butanoicacid tert-butyl ester: The latter 2-oxazolidinone derivative (4.02 g,10.5 mmol) was reacted with lithium hydroxide-hydrogen peroxideaccording to the procedure of example 2, section (g) to give themonoprotected dicarboxylic acid of formula 2, i.e. the 4-tert-butylester of 2(R)-(4-thiazolylmethyl)butanedioic acid. Subsequent couplingof the latter compound (2.83 g, 10.4 mmol) with2(S)-amino-1-cyclohexyl-6-methyl-3(R),4(S)-heptanediol hydrochloride(3.21 g, 11.5 mmol) according to the coupling procedure of example 2,section (g) gave the desired protected amido acid as a white solid (3.75g, 72%); ¹ H NMR(CDCl₃) δ8.70 (s, 1H), 7.10 (s,1H), 5.96 (d, J=8.3Hz,1H), 4.40-4.25 (m,2H), 3.40-2.70 (m,6H), 2.40 (dd, J=4.4 Hz,16.8Hz,1H), 1.95-1.10 (m,17H), 1.40 (s,9H), 0.90 (d, J=6.6 Hz,3H), 0.80 (d,J=6.4 Hz,3H).

(d) The title compound: Under a N₂ atmosphere, TFA (6 mL) was added to acooled solution (0°) of the product of section (c) of this example (3.7g, 7.45 mmol) in CH₂ Cl₂ (30 mL). After the addition, the reactionmixture was stirred at room temperature for 5.5 h. Another portion ofTFA (6 mL) was added to the reaction mixture at 0°. The mixture wasstirred at room temperature for 3 h. Thereafter, the mixture was dilutedwith Et₂ O and concentrated to dryness under reduced pressure to givethe corresponding deprotected amido acid (4.70 g).

The latter compound was used for the following coupling step withoutfurther purification. The latter compound (1.50 g, 3.40 mmol) wasdissolved in DMF (18 mL). BOP•PF₆ (1.80 g, 4.08 mmol),(S)-N,N-dimethyl-2-[(1-phenylethyl)amino]acetamide [0.98 g, 4.76 mmol,described in example 1, section (a)] and DIPEA (1.78 mL, 10.2 mmol) wereadded serially to the solution. The mixture was stirred at roomtemperature for 16 h. Thereafter, the mixture was diluted with EtOAc,washed with a saturated aqueous solution of NaHCO₃, H₂ O and then brine,dried (MgSO₄) and concentrated under reduced pressure. The residue waspurified by flash chromatography (SiO₂, eluent: (EtOH2-EtOAc-hexane,1:5:5) to give the title compound as a white solid (857 mg, 40%); ¹ HNMR (400 MHz, CDCl₃) (approximately a 1:1 mixture of rotamers) δ8.79 and8.76 (2s,1H), 7.37-7.18 (m,6H), 7.07 (broad d, J=8 Hz,1H), 6.05 and 5.12(2q, J=7.0 Hz,7.0 Hz,1H), 4.40 and 4.20 (2m, 1H), 4.37, 3.24 and 3.85,3.73 (4d, J=16.2 Hz,16.2 Hz,17.9 Hz,17.9 Hz, 2H), 3.50-3.10 (m,5H),2.93, 2.92, 2.90 and 2.87 (4s,6H), 2.67 (dd, J=10.2 Hz,17 Hz,1H), 2.54(dd, J=4.8 Hz,17 Hz,1H), 1.98-1.85 (m,2H), 1.85-1.50 (m,1H), 1.58 and1.36 (2d, J=6.9 Hz,7.1 Hz, 3H),1.45-1.10 (m,8H), 0.93 (d, J=6.7 Hz,3H),0.91 and 0.84 (2d, J=6.5 Hz, 6.6 Hz, 3H); FAB mass spectrum, m/z: 629(M+H)⁺, 651 (M+Na)⁺ ; [α]_(D) ²⁵ -55.3° (c 1.00, MeOH).

EXAMPLE 5 Preparation of N⁴ -(Cyclohexylmethyl)-N⁴-(2-morpholino-2-oxoethyl)-N¹-[1(S)-(cyclohexylmethyl)-(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-(cyclopropylmethyl)butanediamide

(a) 3-(3-Cyclopropyl-1-oxopropyl)-4(S)-(1-methylethyl)-2-oxazolidinone:A solution of mixed anhydride was prepared by adding, under N₂, pivoloylchloride (14.8 mL, 120 mmol) over a period of 5 min to a cooled solution(0°) of 4-pentenoic acid (12.3 mL, 120 mmol) and N-methylmorpholine(15.4 mL, 140 mmol). The mixture was stirred at 0° for 30 min.Meanwhile, a second solution was prepared by adding dropwise under N₂ a1.4M solution of butyllithium in hexane (71 mL, 100 mmol) to a stirredcooled solution (-78°) of (S)-4-(1-methylethyl)-2-oxazolidinone (12.9 g,100 mmol) in dry THF (300 mL) over a period of 45 min. (Note: Theagitation was done by an overhead stirrer.) After stirring for 15 min at-78°, the latter solution was added by cannulation to the stirredsolution of the mixed anhydride at -78° over a period of 20 min. Themixture was stirred for an additional 30 min at the same temperature. Asaturated aqueous solution of NH₄ Cl (50 mL) was added and the mixturewas allowed to warm to room temperature. The mixture was diluted with H₂O (300 mL). The organic layer was separated. The aqueous layer wasextracted with EtOAc (3×). The combined organic phases were dried (Na₂SO₄) and evaporated to dryness under reduced pressure to give an oilyresidue [i.e.4(S)-(1-methylethyl)-3-(1-oxo-4-pentenyl)-2-oxazolidinone].

The latter oil was dissolved in 175 mL of a 0.4M Et₂ O solution ofdiazomethane. The resulting solution was cooled to 0°. Palladium(II)acetate (112 mg, 0.5 mmol) was added to the cooled solution. Thesolution bubbled vigorously. After the bubbling subsided, additionalpalladium(II) acetate (112 mg, 0.5 mmol) and the Et₂ O solution ofdiazomethane (175 mL) were added and the ensuing bubbling was allowed tosubside. The latter addition was repeated two more times. (The totalamount of diazomethane solution added was 700 mL.) The mixture wasfiltered through diatomaceous earth. The filtrate was concentrated underreduced pressure. The residual oil was purified by chromatography (SiO₂,eluent: EtOAc-hexane, 1:4) followed by distillation (100° at 0.05 mm Hg)to give the desired 3-(3-cyclopropyl-1-oxopropyl)-2-oxazolidinonederivative (20.0 g, 89%); ¹ H NMR(CDCl₃) δ4.41 (complex m,1H), 4.28 (d,J=9.1 Hz,1H), 4.20 (dd, J=3.4 Hz,8.8 Hz,1H), 3.05 (m,2H), 2.36 (m,1H),1.55 (q, J=7.3 Hz,2H), 0.91 (d, J=7.2 Hz,3H), 0.87 (d, J=7.1 Hz,3H),0.89 (m,1H), 0.43 (m,2H), 0.08 (m,2H).

(b)3-[4-tert-Butoxy-1,4-dioxo-2(R)-(cyclopropylmethyl)butyl]-4(S)-(1-methylethyl)-2-oxazolidinone:A 1.4M solution of butyllithium in hexane (70.0 mL, 97.6 mmol) was addedover a period of 20 min to a cooled solution (0°) of diisopropylamine(15.0 mL, 106 mmol) in dry THF (150 mL). After stirring at 0° for 15min, the solution was cooled to -78°. A solution of the product ofsection (a) of this example (20.0 g, 88.8 mmol) in THF (40 mL) was addedto the cooled solution over 45 min. The mixture was stirred for 1 h at-78°. 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (23.6 mL, 195mmol) and then over a period of 10 min a solution of tert-butyl2-bromoacetate (15.1 mL, 93.2 mmol) in THF (20 mL) were added seriallyto the mixture. After stirring for 1.5 h at -78°, the reaction mixturewas quenched with a saturated aqueous solution of NH₄ Cl and thenallowed to warm to room temperature. The mixture was diluted with EtOAc(250 mL). The organic layer was separated, washed with 5% (w/v) aqueouscitric acid (3×), a saturated aqueous solution of NaHCO₃ (2×) and brine,dried (Na₂ SO₄) and concentrated to dryness under reduced pressure. Theresidual oil was crystallized from EtOAc/hexane to give the desiredoxazolidine derivative as colorless crystals (21.7 g, 72%); mp104°-105°; [α]_(D) ²³ +52.8° (c 1.02, CHCl₃).

(c) The protected amide,3(R)-(cyclopropylmethyl)-4-{[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]amino}-4-oxobutanoicacid tert-butyl ester: Following the procedure of section (g) of example2, the product of section (b) of this example (10.2 g, 30 mmol) wasreacted with lithium hydroxide-hydrogen peroxide to give the desiredmonoprotected dicarboxylic acid, i.e. the 4-tert-butyl ester of2(R)-(cyclopropylmethyl)butanedioic acid, as a colorless oil (6.65 g,97%); [α]_(D) ²³ +16.1° (c 2.61, CHCl₃).

The latter compound (2.39 g, 10.5 mmol) was coupled with an equivalentamount 2(S)-amino-1-cyclohexyl-6-methyl-3(R),4(S)-heptanediolhydrochloride according the the coupling procedure of section (g) ofexample 2 to give the desired protected amido acid as a whitecrystalline material (3.74 g, 78%) after crystallization fromEtOAc-hexane; mp 138°-139°; ¹ H NMR(CDCl₃) δ5.87 (d, J=8.9 Hz,1H), 4.41(broad s, 1H), 4.32 (dt, J=4.4 Hz,9.1 Hz,1H), 3.22 (broad s,2H),2.68-2.39 (m,2H), 2.00-1.10 (complex m, 22H), 1.44 (s, 9H), 0.93 (d,J=6.7 Hz,2H), 0.83 (d, J=6.5 Hz,3H), 0.75-0.65 (m,1H), 0.48 (m,2H), 0.08(broad m, 1H).

(d) The title compound: The product of section (c) of this example (329mg, 0.72 mmol) was deprotected with TFA (1.2 mL) in anhydrous CH₂ Cl₂(2.4 mL) at 0° for 10 min and then at room temperature for 1.5 h to give(after evaporation of the volatiles under reduced pressure) a crudeproduct (369 mg). The crude product was triturated several times withEt₂ O to give3(R)-(cyclopropylmethyl)-4-{[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]amino}-4-oxobutanoicacid as a white solid (193 mg, 67%).

The latter compound (125 mg, 0.31 mmol),4-{2-[(cyclohexylmethyl)amino]-1-oxoethyl]morpholine (94.5 mg, 0.39mmol, described in example 1) and DIPEA (69.1 mg, 0.53 mmol) weredissolved in DMF (1.6 mL). BOP•PF₆ (153 mg, 0.35 mmol) was added to thesolution. The reaction mixture was stirred at room temperautre for 100min. Thereafter, the reaction mixture was diluted with EtOAc, washedsuccessively with 1N aqueous HCl, H₂ O, a saturated aqueous solution ofNaHCO₃ and brine, dried (MgSO₄) and concentrated to dryness underreduced pressure. The residue was purified by flash chromatography(SiO₂, eluent: EtOAc) to give the title compound as a white solid (175mg, 90%); ¹ H NMR(CDCl₃) δ (>4:1 mixture of rotamers) major rotamer:6.42 (broad d, J=8.2 Hz,1H), 4.32 (d, J=15.8 Hz,1H), 4.25-4.11 (m,1H),3.85 (d, J=15.8 Hz,1H), 3.77-3.65 (m,4H), 3.65-3.54 (m,2H), 3.50-3.39(m,2H), 3.32-3.11 (m,4H), 2.97-2.81 (m,1H), 2.74-2.64 (m,2H), 1.99-0.97(m,29H), 0.92 (d, J=6.6 Hz,3H), 0.83 (d, J=6.5 Hz,3H), 0.77-0.62 (m,1H),0.53-0.41 (m,2H), 0.16-0.04 (m,2H); FAB mass spectrum, m/z: 620 (M+H)⁺,642 (M+Na)⁺ ; [α]_(D) ²⁵ -22.8° (c 1.00, MeOH).

By applying the appropriate intermediates, the serial coupling anddeprotection procedure illustrated by examples 2, 3, 4 and 5 can be usedto prepare other compounds of formula 1, such a those exemplified in thetable of the following example.

EXAMPLE 6 Plasma Renin Assay

The ability of the compounds of formula 1 to inhibit human renin can bedemonstrated in the plasma renin assay. The assay is performed asfollows: The test compound (i.e. the inhibitor) is dissolved indimethylsulfoxide (1 mM stock solution) and diluted with an aqueousbuffer solution of 270 mM 2-(N-morpholino)ethanesulfonic acid and 1%human serum albumin (pH 5.85, also containing dimercaprol and8-hydroxyquinoline sulfate in accordance with the instructions of theRIA kit noted below) to give an assay mixture in which the finaldimethylsulfoxide content is 1% (v/v).

A human plasma pool is used as the source of both the substrate(angiotensinogen) and the enzyme (renin). The reaction is initiated bythe addition of 50 μL of human plasma pool to 50 μL of variousconcentrations of inhibitor in the 1% dimethylsulfoxide assay buffer.The plasma renin activity is measured by the amount of angiotensin Igenerated at pH 6.0 following a 2 h incubation at 37°.

Quantitation of angiotensin I is performed by radioimmunoassay (RIA kitfrom New England Nuclear-Dupont, Mississauga, ON, Canada). The enzymaticactivity of renin is expressed in ng of angiotensin I generated (/mL/2h). The extent of inhibition of the reaction is determined from theamount of angiotensin I generated in reference to a control preparedwithout inhibitor. Nonlinear regression analysis is used to calculatethe IC₅₀ values, i.e. the molar concentration of the test compoundrequired to cause a 50% inhibition of the enzyme activity.

The compounds of formula 1 exhibited IC₅₀ 's in the range of 10⁻⁶ to10⁻⁹ molar in this assay. The following table exemplifies resultsobtained for compounds of formula 1.

                  TABLE                                                           ______________________________________                                                               FAB/MS     IC.sub.50                                   Compound of Formula 1  (M + H).sup.+                                                                            (nM)                                        ______________________________________                                        1.  N.sup.4 -benzyl-N.sup.4 -(2-morpholino-2-oxoeth-                                                     614        94                                          yl)-N.sup.1 -[1(S)-(cyclohexylmethyl)-                                        2(R),3(S)-dihydroxy-5-methylhexyl]-                                           2(R)-(cyclopropylmethyl)butanedi-                                             amide                                                                     2.  N.sup.4 -benzyl-N.sup.4 -[2-(dimethylamino)-2-                                                       572        56                                          oxoethyl]-N.sup.1 -[1(S)-(cyclohexylmeth-                                     yl)-2(R),3(S)-dihydroxy-5-                                                    methylhexyl]-2(R)-(cyclopropylmeth-                                           yl)butanediamide                                                          3.  N.sup.4 -[2-(dimethylamino)-2-oxoethyl]-                                                             586        59                                          N.sup.4 -(2-phenylethyl)-N.sup.1 -[1(S)-                                      (cyclohexylmethyl)-2(R),3(S)-                                                 dihydroxy-5-methylhexyl]-2(R)-                                                (cyclopropylmethyl)butanediamide                                          4.  N.sup.4 -[2-(dimethylamino)-2-oxoethyl]-                                                             600        220                                         N.sup.4 -(3-phenylpropyl)-N.sup.1 -[1(S)-(cyclo-                              hexylmethyl)-2(R),3(S)-dihydroxy-5-                                           methylhexyl]-2(R)-(cyclopropylmeth-                                           yl)butanediamide                                                          5.  N.sup.4 -benzyl-N.sup.4 -{2-[methyl(1,1-                                                             614        290                                         dimethylethyl)amino]-2-oxoethyl}-N.sup.1 -                                    [1(S)-(cyclohexylmethyl)-2(R),3(S)-                                           dihydroxy-5-methylhexyl]-2(R)-                                                (cyclopropylmethyl)butanediamide                                          6.  N.sup.4 -benzyl-N.sup.4 -[2-(methylamino)-2-                                                         558        350                                         oxoethyl]-N.sup.1 -[1(S)-(cyclohexyl-                                         methyl)-2(R),3(S)-dihydroxy-5-                                                methylhexyl]-2(R)-(cyclopropylmeth-                                           yl)butanediamide                                                          7.  N.sup.4 -(2-amino-2-oxoethyl)-N.sup.4 -benzyl-N.sup.1 -                                              544        395                                         [1(S)-(cyclohexylmethyl)-2(R),3(S)-                                           dihydroxy-5-methylhexyl]-2(R)-                                                (cyclopropylmethyl)-butanediamide                                         8.  N.sup.4 -benzyl-N.sup.4 -{2-[(methoxy)methyl-                                                        588        66                                          amino]-2-oxoethyl}-N.sup.1 -[1(S)-(cyclo-                                     hexylmethyl)-2(R),3(S)-dihydroxy-5-                                           methylhexyl]-2(R)-(cyclopropylmeth-                                           yl)butanediamide                                                          9   N.sup.4 -[2-(dimethylamino)-2-oxoethyl]-                                                             622        66                                          N.sup.4 -(1-naphthylmethyl)-N.sup.1 -[1(S)-                                   (cyclohexylmethyl)-2(R),3(S)-                                                 dihydroxy-5-methylhexyl]-2(R)-                                                (cyclopropylmethyl)butanediamide                                          10. N.sup.4 -[2-(dimethylamino)-2-oxoethyl]-                                                             602        440                                         N.sup.4 -[(4-methoxyphenyl)methyl]-N.sup.1 -                                  [1(S)-(cyclohexylmethyl)-2(R),3(S)-                                           dihydroxy-5-methylhexyl]-2(R)-                                                (cyclopropylmethyl)butanediamide                                          11. N.sup.4 -benzyl-N.sup.4 -[2-(diethylamino)-2-                                                        600        140                                         oxoethyl]-N.sup.1 -[1(S)-(cyclohexylmeth-                                     yl)-2(R),3(S)-dihydroxy-5-methyl-                                             hexyl]-2(R)-(cyclopropylmethyl)-                                              butanediamide                                                             12. N.sup.4 -benzyl-N.sup.4 -{2-{methyl[2-(2-pyri-                                                       663        34                                          dinyl)ethyl]amino}-2-oxoethyl}-N.sup.1 -                                      [1(S)-(cyclohexylmethyl)-2(R),3(S)-                                           dihydroxy-5-methylhexyl]-2(R)-                                                (cyclopropylmethyl)butanediamide                                          13. N.sup.4 -[2-(dimethylamino)-2-oxoethyl]-                                                             573        120                                         N.sup.4 -(2-pyridinylmethyl)-N.sup.1 -[1(S)-                                  (cyclohexylmethyl)-2(R),3(S)-                                                 dihydroxy-5-methylhexyl]-2(R)-                                                (cyclopropylmethyl)butanediamide                                          14. N.sup.4 -[2-(dimethylamino)-2-oxoethyl]-                                                             573        350                                         N.sup.4 -(3-pyridinylmethyl)-N.sup.1 -[1(S)-                                  (cyclohexylmethyl)-2(R),3(S)-                                                 dihydroxy-5-methylhexyl]-2(R)-                                                (cyclopropylmethyl)butanediamide                                          15. N.sup.4 -{2-{methyl{2-[methyl(morpholino-                                                            800        0.5                                         carbonyl)amino]ethyl}amino}-2-                                                oxoethyl}-N.sup.4 -[1(S)-phenylethyl]-N.sup.1 -                               [1(S)-(cyclohexylmethyl)-2(R),3(S)-                                           dihydroxy-5-methylhexyl]-2(R)-[(2-                                            amino-4-thiazolyl)methyl]butanedi-                                            amide                                                                     16. N.sup.4 -[2-(dimethylamino)-2-oxoethyl]-                                                             586        460                                         N.sup.4 -[1(R)-phenylethyl]-N.sup.1 -[1(S)-                                   (cyclohexylmethyl)-2(R),3(S)-                                                 dihydroxy-5-methylhexyl]-2(R)-                                                (cyclopropylmethyl)butanediamide                                          17. N.sup.4 -[2-(dimethylamino)-2-oxoethyl]-                                                             586        34                                          N.sup.4 -[1(S)-phenylethyl]-N.sup.1 -[1(S)-                                   (cyclohexylmethyl)-2(R),3(S)-                                                 dihydroxy-5-methylhexyl]-2(R)-                                                (cyclopropylmethyl)butanediamide                                          18. N.sup.4 -[2-(dimethylamino)-2-oxoethyl]-                                                             636        170                                         N.sup.4 -[1(S)-(1-naphthylethyl)]-N.sup.1 -                                   [1(S)-(cyclohexylmethyl)-2(R),3(S)-                                           dihydroxy-5-methylhexyl]-2(R)-                                                (cyclopropylmethyl)butanediamide                                          19. N.sup.4 -[2-(dimethylamino)-2-oxoethyl]-                                                             600        69                                          N.sup.4 -[2(R)-phenylpropyl]-N.sup.1 -[1(S)-                                  (cyclohexylmethyl)-2(R),3(S)-                                                 dihydroxy-5-methylhexyl]-2(R)-                                                (cyclopropylmethyl)butanediamide                                          20. N.sup.4 -[2-(dimethylamino)-2-oxoethyl]-                                                             600        37                                          N.sup.4 -(2(S)-phenylpropyl]-N.sup.1 -(1(S)-                                  (cyclohexylmethyl)-2(R),3(S)-                                                 dihydroxy-5-methylhexyl]-2(R)-                                                (cyclopropylmethyl)butanediamide                                          21. N.sup.4 -[2-(dimethylamino)-2-oxoethyl]-                                                             614        150                                         N.sup.4 -(2-methyl-2-phenylpropyl)-N.sup.1 -                                  [1(S)-(cyclohexylmethyl)-2(R),3(S)-                                           dihydroxy-5-methylhexyl]-2(R)-                                                (cyclopropylmethyl)butanediamide                                          22. N.sup.4 -[1(S)-phenylethyl]-N.sup.4 -{2-{meth-                                                       677        20                                          yl[2-(2-pyridinyl)ethyl]-amino}-2-                                            oxoethyl}-N.sup.1 -(1(S)-(cyclohexylmeth-                                     yl)-2(R),3(S)-dihydroxy-5-methyl-                                             hexyl]-2(R)-(cyclopropylmethyl)-                                              butanediamide                                                             23. N.sup.4 -{2-{[2-(dimethylamino)ethyl]meth-                                                           643        26                                          ylamino}-2-oxoethyl}-N.sup.4 -[1(S)-phen-                                     ylethyl]-N.sup.1 -[1(S)-(cyclohexylmeth-                                      yl)-2(R),3(S)-dihydroxy-5-methyl-                                             hexyl]-2(R)-(cyclopropylmethyl)-                                              butanediamide                                                             24. N.sup.4 -{2-{[2-(diethylamino)ethyl]meth-                                                            671        61                                          ylamino}-2-oxoethyl}-N.sup.4 -[1(S)-phen-                                     ylethyl]-N.sup.1 -[1(S)-(cyclohexylmeth-                                      yl)-2(R),3(S)-dihydroxy-5-methyl-                                             hexyl]-2(R)-(cyclopropylmethyl)-                                              butanediamide                                                             25. N.sup.4 -[2-(dimethylamino)-2-oxoethyl]-                                                             574        34                                          N.sup.4 -[1(S)-phenylethyl]-N.sup.1 -[1(S)-                                   (cyclohexylmethyl)-2(R),3(S)-                                                 dihydroxy-5-methylhexyl]-2(R)-                                                propylbutanediamide                                                       26. N.sup.4 -benzyl-N.sup.4 -{2-{methyl[2-(2-                                                            651        29                                          pyridinyl)ethyl]amino}-2-oxoethyl}-                                           N.sup.1 -[1(S)-(cyclohexylmethyl)-                                            2(R),3(S)-dihydroxy-5-methylhexyl]-                                           2(R)-propylbutanediamide                                                  27. N.sup.4 -[2-(dimethylamino)-2-oxoethyl]-                                                             612         6                                          N.sup.4 -(1(S)-phenylethyl]-N.sup.1 -[1(S)-                                   (cyclohexylmethyl)-2(R),3(S)-                                                 dihydroxy-5-methylhexyl]-2(R)-(1H-                                            imidazol-4-ylmethyl)butanediamide                                         28. N.sup.4 -[2-(dimethylamino)-2-oxoethyl]-                                                             644        1.3                                         N.sup.4 -[1(S)-phenylethyl]-N.sup.1 -[1(S)-                                   (cyclohexylmethyl)-2(R),3(S)-dihy-                                            droxy-5-methylhexyl]-2(R)-[(2-amino-                                          4-thiazolyl)methyl]butanediamide                                          29. N.sup.4 -benzyl-N.sup.4 -{2-{methyl[2-(4-                                                            663        68                                          pyridinyl)ethyl]amino}-2-oxoethyl}-                                           N.sup.1 -[1(S)-(cyclohexylmethyl)-                                            2(R)3(S)-dihydroxy-5-methylhexyl]-                                            2(R)-(cyclopropylmethyl)butanedi-                                             amide                                                                     30. N.sup.4 -[2-(dimethylamino)-2-oxoethyl]-                                                             629        2.5                                         N.sup.4 -[1(S)-phenylethyl]-N.sup.1 -[1(S)-                                   (cyclohexylmethyl)-2(R),3(S)-                                                 dihydroxy-5-methylhexyl]-2(R)-(4-                                             thiazolylmethyl)butanediamide                                             31. N.sup.4 -(cyclohexylmethyl)-N.sup.4 -(2-                                                             578        13                                          (dimethylamino)-2-oxoethyl]-N.sup.1 -                                         [1(S)-(cyclohexylmethyl)-2(R),3(S)-                                           dihydroxy-5-methylhexyl]-2(R)-                                                (cyclopropylmethyl)butanediamide                                          32. N.sup.4 -(2-(dimethylamino)-2-oxoethyl]-                                                             628        13                                          N.sup.4 -(1(S)-phenylethyl]-N.sup.1 -[1(S)-                                   (cyclohexylmethyl)-2(R),3(S)-                                                 dihydroxy-5-methylhexyl]-2(S)-(2-                                             thienylmethyl)butanediamide                                               33. N.sup.4 -[1(S)-phenylethyl-N.sup.4 -(2-morpho-                                                       628        120                                         lino-2-oxoethyl)-N.sup.1 -1(S)-(cyclo-                                        hexylmethyl)-2(R),3(S)-dihydroxy-5-                                           methylhexyl]-2(R)-(cyclopropylmeth-                                           yl)butanediamide                                                          34. N.sup.4 -benzyl-N.sup.4 -{2-{methyl[2-(2-                                                            705        13                                          pyridinyl)ethyl]amino}-2-oxoethyl}-                                           N.sup.1 -[1(S)-(cyclohexylmethyl)-                                            2(R),3(S)-dihydroxy-5-methylhexyl]-                                           2(S)-(2-thienylmethyl)butanediamide                                       35. N.sup.4 -(cyclohexylmethyl)-N.sup.4 -(2-                                                             620         8                                          morpholino-2-oxoethyl)-N.sup.1 -[1(S)-                                        (cyclohexylmethyl)-2(R),3(S)-                                                 dihydroxy-5-methylhexyl]-2(R)-                                                (cyclopropylmethyl)butanediamide                                          36. N.sup.4 -(cyclohexylmethyl)-N.sup.4 -[2-                                                             621        1.5                                         (dimethylamino)-2-oxoethyl]-N.sup.1 -                                         [1(S)-(cyclohexylmethyl)-2(R),3(S)-                                           dihydroxy-5-methylhexyl]-2(R)-(4-                                             thiazolylmethyl)butanediamide                                             37. N.sup.4 -(cyclohexylmethyl)-N.sup.4 -[2-                                                             621        1.6                                         (dimethylamino)-2-oxoethyl]-N.sup.1 -                                         [1(S)-(cyclohexylmethyl)-2(R),3(S)-                                           dihydroxy-5-methylhexyl]-2(S)-(2-                                             Thiazolylmethyl)butanediamide                                             38. N.sup.4 -(1(S)-cyclohexylethyl)-N.sup.4 -[2-                                                         592        8.3                                         (dimethylamino)-2-oxoethyl]-N.sup.1 -                                         [1(S)-(cyclohexylmethyl)-2(R),3(S)-                                           dihydroxy-5-methylhexyl]-2(R)-                                                (cyclopropylmethyl)butanediamide                                          39. N.sup.4 -(cyclohexylmethyl)-N.sup.4 -(2-                                                             663        1.6                                         morpholino-2-oxoethyl)-N.sup.1 -[1(S)-                                        (cyclohexylmethyl)-2(R),3(S)-                                                 dihydroxy-5-methylhexyl]-2(S)-(2-                                             thiazolylmethyl)butanediamide                                             40. N.sup.4 -[2-(dimethylamino)-2-oxoethyl]-                                                             643        6.7                                         N.sup.4 -[2 (S)-phenylpropyl]-N.sup.1 -[1(S)-                                 (cyclohexylmethyl)-2(R),3(S)-                                                 dihydroxy-5-methylhexyl]-2(S)-(2-                                             thiazolylmethyl)butanediamide                                             41. N.sup.4 -benzyl-N.sup.4 -{2-{methyl[2-(2-                                                            706        3.5                                         pyridinyl)ethyl]amino}-2-oxoethyl}-                                           N.sup.1 -[1(S)-(cyclohexylmethyl)-                                            2(R),3(S)-dihydroxy-5-methylhexyl]-                                           2(S)-(2-thiazolylmethyl)butanedi-                                             amide                                                                     42. N.sup.4 -[2-(dimethylamino)-2-oxoethyl]-                                                             625        55                                          N.sup.4 -[1(S)-phenylethyl]-N.sup.1 -[1(S)-                                   (cyclohexylmethyl)-2(S)-hydroxy-2-                                            (1,5,5-trimethyl-2-oxopyrrolidin-                                             3(S)-yl)ethyl]-2(R)-(cyclopropyl-                                             methyl)butanediamide                                                      43. N.sup.4 -[2-(dimethylamino)-2-oxoethyl]-                                                             628        6.8                                         N.sup.4 -[1(S)-phenylethyl]-N.sup.1 -[1(S)-                                   (cyclohexylmethyl)-2(R),3(S)-                                                 dihydroxy-(3-cyclopropylpropyl)]-                                             2(R)-[(2-amino-4-thiazolyl)methyl]-                                           butanediamide                                                             44. N.sup.4 -[2-(dimethylamino)-2-oxoethyl]-                                                             683        2.4                                         N.sup.4 -[1(S)-phenylethyl]-N.sup.1 -[1(S)-                                   (cyclohexylmethyl)-2(S)-hydroxy-2-                                            (1,5,,5-trimethyl-2-oxopyrrolidin-                                            3(S)-yl)ethyl]-2(R)-[(2-amino-4-                                              thiazolyl)methyl]butanediamide                                            45. N.sup.4 -[2-(dimethylamino)-2-oxoethyl]-                                                             644        16                                          N.sup.4 -[1(S)-phenylethyl]-N.sup.4 -[1(S)-                                   (cyclohexylmethyl)-2(R)-hydroxy-3-                                            (1-methylethoxy)-3-oxopropyl]-2(R)-                                           [(2-amino-4-thiazolyl)methyl]-                                                butanediamide                                                             46. N.sup.4 -(cyclohexylmethyl)-N.sup.4 -{2-{methyl-                                                     669        12                                          [2-(2-pyridinyl)-ethyl]amino}-2-                                              oxoethyl}-N.sup.1 -[1(S)-(cyclohexylmeth-                                     yl)-2(R),3(S)-dihydroxy-5-                                                    methylhexyl]-2(R)-(cyclopropylmeth-                                           yl)butanediamide                                                          47. N.sup.4 -(cyclohexylmethyl)-N.sup.4 -[2-                                                             635        18.5                                        (dimethylamino)-2-oxoethyl]-N.sup.1 -                                         [1(S)-(cyclohexylmethyl)-2(R),3(S)-                                           dihydroxy-5-methylhexyl]-2(R)-[(2-                                            methyl-4-thiazolyl)methyl]butanedi-                                           amide                                                                     48. N.sup.4 -(cyclohexylmethyl)-N.sup.4 -[2-                                                             636        0.9                                         (dimethylamino)-2-oxoethyl]-N.sup.1 -                                         [1(S)-(cyclohexylmethyl)-2(R),3(S)-                                           dihydroxy-5-methylhexyl]-2(R)-[(2-                                            amino-4-thiazolyl)methyl]butanedi-                                            amide                                                                     49. N.sup.4 -(cyclohexylmethyl)-N.sup.4 -2-                                                              678        1.5                                         morpholino-2-oxoethyl)-N.sup.4 -[1(S)-                                        (cyclohexylmethyl)-2(R),3(S)-                                                 dihydroxy-5-methylhexyl]-2(R)-[(2-                                            amino-4-thiazolyl)methyl]butanedi-                                            amide                                                                     50. N.sup.4 -(cyclohexylmethyl)-N.sup.4 -{2-{methyl-                                                     727        2.2                                         [2-(2-pyridinyl)ethyl]-amino}-2-                                              oxoethyl}-N.sup.1 -[1(S)-(cyclohexylmeth-                                     yl)-2(R),3(S)-dihydroxy-5-methyl-                                             hexyl]-2(R)-[(2-amino-4-thiazol-                                              yl)methyl]butanediamide                                                   51. N.sup.4 -[2-(dimethylamino)-2-oxoethyl]-                                                             587        145                                         N.sup.4 -[2-(2-pyridinyl)ethyl]-N.sup.1 -(1(S)-                               (cyclohexylmethyl)-2(R),3(S)-                                                 dihydroxy-5-methylhexyl]-2(R)-                                                (cyclopropylmethyl)butanediamide                                          52. N.sup.4 -benzyl-N.sup.1 -[2-(dimethylamino)-2-                                                       630         3                                          oxoethyl)-N.sup.1 -[1(S)-(cyclohexylmeth-                                     yl)-2(R),3(S)-dihydroxy-5-methyl-                                             hexyl]-2(R)-[(2-amino-4-thiazolyl)-                                           methyl]butanediamide                                                      53. N.sup.4 -benzyl-N.sup.4 -{2-{methyl[2-(2-pyri-                                                       706        2.5                                         dinyl)ethyl]amino}-2-oxoethyl}-N.sup.1 -                                      [1(S)-(cyclohexylmethyl)-2(R),3(S)-                                           dihydroxy-5-methylhexyl]-2(R)-(4-                                             thiazolylmethyl)butanediamide                                             54. N.sup.4 -[2-(dimethylamino)-2-oxoethyl]-                                                             629         4                                          N.sup.4 -[1(S)-phenylethyl]-N.sup.1 -[1(S)-                                   (cyclohexylmethyl)-2(R),3(S)-                                                 dihydroxy-5-methylhexyl]-2(S)-(2-                                             thiazolylmethyl)butanediamide                                             55. N.sup.4 -(cyclohexylmethyl)-N.sup.4 -[2-(di-                                                         614        16                                          methylamino)-2-oxoethyl]-N.sup.1 -[1(S)-                                      (cyclohexylmethyl)-2(R),3(S)-                                                 dihydroxy-5-methylhexyl]-2(R)-                                                (phenylmethyl)butanediamide                                               56. N.sup.4 -{{1(S),2(R),4(S)-and                                                                        633         2                                          1(R),2(S),4(R)-{bicyclo[2.2.1]hept-                                           2-yl}methyl}-N.sup.4 -[2-(dimethylamino)-                                     2-oxoethyl]-N.sup.1 -[1(S)-(cyclohexyl-                                       methyl)-2(R),3(S)-dihydroxy-5-                                                methylhexyl]-2(R)-(4-thiazolyl-                                               methyl)butanediamide                                                      57. N.sup.4 -benzyl-N.sup.4 -{2-{methyl[2-(2-                                                            721         1                                          pyridinyl)ethyl]amino}-2-oxoethyl}-                                           N.sup.1 -[1(S)-(cyclohexylmethyl)-                                            2(R),3(S)-dihydroxy-5-methylhexyl]-                                           2(R)-[(2-amino-4-thiazolyl)methyl]-                                           butanediamide                                                             58. N.sup.4 -(cyclohexylmethyl)-N.sup.4 -[2-                                                             615        10                                          (dimethylamino)-2-oxoethyl]-N.sup.1 -                                         [1(S)-(cyclohexylmethyl)-2(R),3(S)-                                           dihydroxy-5-methylhexyl]-2(R)-(3-                                             pyridinylmethyl)butanediamide                                             59. N.sup.4 -(cyclohexylmethyl)-N.sup.4 -(2-                                                             658        10                                          morpholino-2-oxoethyl)-N.sup.1 -[1(S)-                                        (cyclohexylmethyl)-2(R),3(S)-                                                 dihydroxy-5-methylhexyl]-2(R)-(3-                                             pyridinylmethyl)butanediamide                                             60. N.sup.4 -[2-(dimethylamino)-2-oxoethyl]-                                                             644         5                                          N.sup.4 -(2-phenylethyl)-N.sup.1 -[1(S)-                                      (cyclohexylmethyl)-2(R),3(S)-                                                 dihydroxy-5-methylhexyl]-2(R)-[(2-                                            amino-4-thiazolyl)methyl]butanedi-                                            amide                                                                     61. N.sup.4 -[2-(dimethylamino)-2-oxoethyl]-                                                             658        3.5                                         N.sup.4 -[2(S)-phenylpropyl]-N.sup.1 -[1(S)-                                  (cyclohexylmethyl)-2(R),3(S)-                                                 dihydroxy-5-methylhexyl]-2(R)-[(2-                                            amino-4-thiazolyl)methyl]-                                                    butanediamide                                                             62. N.sup.4 -{2-[4-(methoxymethoxy)piperidin-                                                            736         3                                          yl]-2-oxoethyl}-N.sup.4 -(cyclohexyl-                                         methyl)-N.sup.1 -[1(S)-(cyclohexylmethyl)-                                    2(R),3(S)-dihydroxy-5-methylhexyl]-                                           2(R)-[(2-amino-4-thiazolyl)methyl]-                                           butanediamide                                                             63. N.sup.4 -[1(S)-cyclohexylethyl]-N.sup.4 -{2-                                                         741         1                                          {methyl[2-(2-pyridinyl)ethyl]-                                                amino}-2-oxoethyl}-N.sup.1 -[1(S)-(cyclo-                                     hexylmethyl)-2(R),3(S)-dihydroxy-5-                                           methylhexyl]-2(R)-[(2-amino-4-                                                thiazolyl)methyl]butanediamide                                            64. N.sup.4 -[2-(dimethylamino)-2-oxoethyl]-                                                             631        10                                          N.sup.4 -(2 -pyridinylmethyl)-N.sup.1 -[1(S)-                                 (cyclohexylmethyl)-2(R),3(S)-                                                 dihydroxy-5-methylhexyl]-2(R)-[(2-                                            amino-4-thiazolyl)methyl]-                                                    butanediamide                                                             65. N.sup.4 -(cyclohexylmethyl)-N.sup.4 -{2-{methyl-                                                     769        45                                          [2-(2-pyridinyl)ethyl]amino}-2-oxo-                                           ethyl}-N.sup.1 -{1(S)-(cyclohexylmethyl)-                                     2(R)-hydroxy-3-[(l-methyl-1H-                                                 tetrazol-5-yl)thio]propyl}-2(R)-[(2-                                          amino-4-thiazolyl)methyl]-                                                    butanediamide                                                             66. N.sup.4 -(cyclohexylmethyl)-N.sup.4 -{2-{methyl-                                                     706        10                                          [2-(2-pyridinyl)ethyl]amino}-2-                                               oxoethyl}-N.sup.1 -[1(S)-(cyclohexylmeth-                                     yl)-2(R),3(S)-dihydroxy-5-methyl-                                             hexyl]-2(R)-(3-pyridinylmethyl)-                                              butanediamide                                                             67. N.sup.4 -(cyclohexylmethyl)-N.sup.4 -(2-morpho-                                                      657         4                                          lino-2-oxoethyl)-N.sup.1 -[1(S)-(cyclo-                                       hexylmethyl)-2(R),3(S)-dihydroxy-5-                                           methylhexyl]-2(R)-(2-pyridinylmeth-                                           yl)butanediamide                                                          68. N.sup.4 -(cyclohexylmethyl)-N.sup.4 -[2-(dimeth-                                                     615         4                                          ylamino)-2-oxoethyl]-N.sup.1 -[1(S)-                                          (cyclohexylmethyl)-2(R),3(S)-                                                 dihydroxy-5-methylhexyl]-2(R)-(2-                                             pyridinylmethyl)butanediamide                                             69. N.sup.4 -(cyclopentylmethyl)-N.sup.4 -[2-                                                            601        32                                          (dimethylamino)-2-oxoethyl]-N.sup.1 -                                         [1(S)-(cyclohexylmethyl)-2(R),3(S)-                                           dihydroxy-5-methylhexyl]-2(R)-(3-                                             pyridinylmethyl)butanediamide                                             70. N.sup.4 -(cycloheptylmethyl)-N.sup.4 -[2-                                                            630         7                                          (dimethylamino)-2-oxoethyl]-N.sup.1 -                                         [1(S)-(cyclohexylmethyl)-2(R),3(S)-                                           dihydroxy-5-methylhexyl]-2(R)-(3-                                             pyridinylmethyl)butanediamide                                             71. N.sup.4 -(cyclopentylmethyl)-N.sup.4 -{2-                                                            713         1                                          {methyl[2-(2-pyridinyl)ethyl]-                                                amino}-2-oxoethyl]-N.sup.1 -[1(S)-(cyclo-                                     hexylmethyl)-2(R),3(S)-dihydroxy-5-                                           methylhexyl]-2(R)-[(2-amino-4-                                                thiazolyl)methyl]butanediamide                                            72. N.sup.4 -{2-{methyl[2-(2-pyridinyl)ethyl]-                                                           727         2                                          amino}-2-oxoethyl}-N.sup.4 -(2-thienyl-                                       methyl)-N.sup.1 -[1(S)-(cyclohexylmethyl)-                                    2(R),3(S)-dihydroxy-5-methylhexyl]-                                           2(R)-[(2-amino-4-thiazolyl)methyl]-                                           butanediamide                                                             73. N.sup.4 -[2-(dimethylamino)-2-oxoethyl]-                                                             658         3                                          N.sup.4 -[(3,5-dimethylphenyl)methyl]-N.sup.1 -                               [1(S)-(cyclohexylmethyl)-2(R),3(S)-                                           dihydroxy-5-methylhexyl]-2(R)-[(2-                                            amino-4-thiazolyl)methyl]butanedi-                                            amide                                                                     74. N.sup.4 -(cyclohexylmethyl)-N.sup.4 -{2-{methyl-                                                     727        18                                          [2-(2-pyridinyl)ethyl]amino}-2-oxo-                                           ethyl}-N.sup.1 -[1(S)-(cyclohexylmethyl)-                                     2(R)-hydroxy-3-(1-methylethoxy)-3-                                            oxopropyl]-2(R)-[(2-amino-4-                                                  thiazolyl)methyl]butanediamide                                            75. N.sup.4 -{2-{methyl[2-(2-pyridinyl)ethyl]-                                                           735         1                                          amino}-2-oxoethyl}-N.sup.4 -[1(S)-                                            phenylethyl]-N.sup.1 -[1(S)-(cyclohexyl-                                      methyl)-2(R),3(S)-dihydroxy-5-                                                methylhexyl]-2(R)-[(2-amino-4-                                                thiazolyl)methyl]butanediamide                                            76. N.sup.4 -(cyclohexylmethyl)-N.sup.4 -{2-                                                             727        0.4                                         {methyl[2-(3-pyridinyl)ethyl]-                                                amino}-2-oxoethyl}-N.sup.1 -[1(S)-(cyclo-                                     hexylmethyl)-2(R),3(S)-dihydroxy-5-                                           methylhexyl]-2(R)-[(2-amino-4-                                                thiazolyl)methyl]butanediamide                                            77  N.sup.4 -(cyclohexylmethyl)-N.sup.4 -{2-                                                             711        36                                          {methyl[2-(2-pyridinyl)ethyl]-                                                amino}-2-oxoethyl}-N.sup.1 -[1(S)-(cyclo-                                     hexylmethyl)-2(S)-hydroxy-5-                                                  methylhexyl]-2(R)-[(2-amino-4-                                                thiazolyl)methyl]butanediamide                                            78. N.sup.4 -(cycloheptylmethyl)-N.sup.4 -[2-                                                            650        0.6                                         (dimethylamino)-2-oxoethyl]-N.sup.1 -                                         [1(S)-(cyclohexylmethyl)-2(R),3(S)-                                           dihydroxy-5-methylhexyl]-2(R)-[(2-                                            amino-4-thiazolyl)methyl]butanedi-                                            amide                                                                     79. N.sup.4 -(2-furanylmethyl)-N.sup.4 -{2-{methyl-                                                      711         1                                          [2-(2-pyridinyl)ethyl)amino}-2-                                               oxoethyl}-N.sup.1 -[1(S)-(cyclohexylmeth-                                     yl)-2(R),3(S)-dihydroxy-5-methyl-                                             hexyl]-2(R)-[(2-amino-4-thiazolyl)-                                           methyl]butanediamide                                                      80. N.sup.4 -(cyclopentylmethyl)-N.sup.4 -(2-morpho-                                                     664         2                                          lino-2-oxoethyl)-N.sup.1 -[1(S)-(cyclo-                                       hexylmethyl)-2(R),3(S)-dihydroxy-5-                                           methylhexyl]-2(R)-[(2-amino-4-                                                thiazolyl)methyl]butanediamide                                            81. N.sup.4 -(cycloheptylmethyl)-N.sup.4 -{2-{meth-                                                      742         1                                          yl[2-(2-pyridinyl)ethyl]amino}-2-                                             oxoethyl}-N.sup.1 -[1(S)-(cyclohexylmeth-                                     yl)-2(R),3(S)-dihydroxy-5-methyl-                                             hexyl]-2(R)-[(2-amino-4-thiazolyl)-                                           methyl]butanediamide                                                      82. N.sup.4 -[(2-fluorophenyl)methyl]-N.sup.4 -{2-                                                       739         3                                          {methyl[2-(2-pyridinyl)ethyl]-                                                amino}-2-oxoethyl}-N.sup.1 -[1(S)-(cyclo-                                     hexylmethyl)-2(R),3(S)-dihydroxy-5-                                           methylhexyl]-2(R)-[(2-amino-4-                                                thiazolyl)methyl]butanediamide                                            83. N.sup.4 -(cyclohexylmethyl)-N.sup.4 -{2-{meth-                                                       792         0.35                                       yl{2-[methyl(morpholinocarbonyl)-                                             amino]ethyl}amino}-2-oxoethyl}-N.sup.1 -                                      [1(S)-(cyclohexylmethyl)-2(R),3(S)-                                           dihydroxy-5-methylhexyl]-2(R)-[(2-                                            amino-4-thiazolyl)methyl]butanedi-                                            amide                                                                     84. N.sup.4 -(2-ethylbutyl)-N.sup.4 -{2-{methyl[2-                                                       715         3                                          (2-pyridinyl)ethyl]amino}-2-oxoeth-                                           yl}-N.sup.1 -[1(S)-(cyclohexylmethyl)-                                        2(R),3(S)-dihydroxy-5-methylhexyl]-                                           2(R)-[(2-amino-4-thiazolyl)methyl]-                                           butanediamide                                                             85. N.sup.4 -(cyclopentylmethyl)-N.sup.4 -[2-                                                            622         1                                          (dimethylamino)-2-oxoethyl]-N.sup.1 -                                         [1(S)-(cyclohexylmethyl)-2(R),3(S)-                                           dihydroxy-5-methylhexyl]-2(R)-[(2-                                            amino-4-thiazolyl)methyl]butanedi-                                            amide                                                                     86. N.sup.4 -{2-{methyl[2-(2-pyridinyl)ethyl]-                                                           728         6                                          amino}-2-oxoethyl}-N.sup.4 -(2-thiazolyl-                                     methyl)-N.sup.1 -[1(S)-(cyclohexylmethyl)-                                    2(R),3(S)-dihydroxy-5-methylhexyl]-                                           2(R)-[(2-amino-4-thiazolyl)methyl]-                                           butanediamide                                                             87. N.sup.4 -(2-cyclopentylethyl)-N.sup.4 -{2-{meth-                                                     727         2                                          yl[2-(2-pyridinyl)ethyl]amino}-2-                                             oxoethyl}-N.sup.1 -[1(S)-(cyclohexylmeth-                                     yl)-2(R),3(S)-dihydroxy-5-methyl-                                             hexyl]-2(R)-[(2-amino-4-thiazolyl)-                                           methyl]butanediamide                                                      88. N.sup.4 -{2-{methyl[2-(2-pyridinyl)ethyl]-                                                           741         4                                          amino}-2-oxoethyl}-N.sup.4 -[(3-methyl-2-                                     thienyl)methyl]-N.sup.4 -[1(S)-(cyclo-                                        hexylmethyl)-2(R),3(S)-dihydroxy-5-                                           methylhexyl]-2(R)-[(2-amino-4-                                                thiazolyl)methyl]butanediamide                                            89. N.sup.4 -(3-furanylmethyl)-N.sup.4 -{2-{methyl-                                                      711         3                                          [2-(2-pyridinyl)ethyl]amino}-2-                                               oxoethyl}-N.sup.1 -[1(S)-(cyclohexylmeth-                                     yl)-2(R),3(S)-dihydroxy-5-methyl-                                             hexyl]-2(R)-[(2-amino-4-thiazolyl)-                                           methyl]butanediamide                                                      90. N.sup.4 -(cyclohexylmethyl)-N.sup.4 -{2-{methyl-                                                     735        0.5                                         (2-morpholinoethyl)amino]-2-oxoeth-                                           yl}-N.sup.1 -[(S)-(cyclohexylmethyl)-                                         2(R),3(S)-dihydroxy-5-methylhexyl]-                                           2(R)-[(2-amino-4-thiazolyl)methyl]-                                           butanediamide                                                             91. N.sup.4 -{2-{methyl[2-(2-pyridinyl)ethyl]-                                                           729         8                                          amino}-2-oxoethyl}-N.sup.4 -(1-propyl-                                        butyl)-N.sup.4 -(S)-(cyclohexylmethyl)-                                       2(R),3(S)-dihydroxy-5-methylhexyl]-                                           2(R)-[(2-amino-4-thiazolyl)methyl]-                                           butanediamide                                                             92. N.sup.4 -{2-{methyl[2-(2-pyridinyl)ethyl]-                                                           744         5                                          amino}-2-oxoethyl}-N.sup.4 -(2-propyl-                                        pentyl)-N.sup.1 -[1(S)-(cyclohexylmethyl)-                                    2(R),3(S)-dihydroxy-5-methylhexyl]-                                           2(R)-[(2-amino-4-thiazolyl)methyl]-                                           butanediamide                                                             93. N.sup.4 -{2-[methyl(2-morpholinoethyl)-                                                              743         2                                          amino]-2-oxoethyl}-N.sup.4 -[1(S)-phenyl-                                     ethyl]-N.sup.1 -[1(S)-(cyclohexylmethyl)-                                     2(R),3(S)-dihydroxy-5-methylhexyl]-                                           2(R)-[(2-amino-4-thiazolyl)methyl]-                                           butanediamide                                                             ______________________________________                                    

Other compounds of formula 1 include:

N⁴ -(2-ethyl-2-methylbutyl)-N⁴-{2-{methyl[2-(2-pyridinyl)ethyl]amino}-2-oxoethyl}-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide,

N⁴ -[2-(dimethylamino)-2-oxoethyl]-N⁴ -[1(S)-phenylethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(S)-hydroxy-5-methylhexyl]-2(R)-(4-thiazolylmethyl)butanediamide,

N⁴ -[2-(dimethylamino)-2-oxoethyl]-N⁴ -[1(S)-phenylethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(S)-hydroxy-5-methylhexyl]-2(S)-(2-thiazolylmethyl)butanediamide,

N⁴ -(cyclohexylmethyl)-N⁴ -[2-(dimethylamino)-2-oxoethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(S)-hydroxy-2-(1,5,5-trimethyl-2-oxopyrrolidin-3(S)-yl)ethyl]-2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide,

N⁴ -(cyclohexylmethyl)-N⁴ -(2-morpholino-2-oxoethyl)-N¹-[1(S)-(cyclohexylmethyl)-2(S)-hydroxy-2-(1,5,5,-trimethyl-2-oxopyrrolidin-3(S)-yl)ethyl]-2(R)-(4-thiazolylmethyl)butanediamide,

N⁴ -(cyclohexylmethyl)-N⁴ -[2-(dimethylamino)-2-oxoethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(S)-hydroxy-3-cyclopropylpropyl]-2(S)-(2-thiazolylmethyl)butanediamide,

N⁴ -(cyclohexylmethyl)-N⁴-{2-{methyl[2-(2-pyridinyl)ethyl]amino}-2-oxoethyl}-N¹-[1(S)-(cyclohexylmethyl-2(S)-hydroxy-3-cyclopropylpropyl]-2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide,

N⁴ -[2-(dimethylamino)-2-oxoethyl]-N⁴ -[1(S)-phenylethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(S)-hydroxy-4-methylpentyl]-2(R)-(4-thiazolylmethyl)butanediamide,

N⁴ -(cyclohexylmethyl)-N⁴ -(2-morpholino-2-oxoethyl)-N¹-[1(S)-(cyclohexylmethyl)-2(S)-hydroxy-4-methylpentyl]-2(S)-(2-thiazolylmethyl)butanediamide,

N⁴ -(cyclohexylmethyl)-N⁴ -(2-morpholino-2-oxoethyl)N¹-[1(S)-(cyclohexylmethyl)-2(R)-hydroxy-3-(1-methylethoxy)-3-oxopropyl]-2(R)-(4-thiazolylmethyl)butanediamide,

N⁴ -(cyclohexylmethyl)-N⁴-{2-{methyl[2-(2-pyridinyl)ethyl]amino}-2-oxoethyl}-N¹-[1(S)-(cyclohexylmethyl)-2(R)-hydroxy-3-(1-methylethoxy)-3-oxopropyl]-2(S)-(2-thiazolylmethyl)butanediamide,

N⁴ -benzyl-N⁴ -{2-[4-(methoxymethoxy)-1-piperidinyl]-2-oxoethyl}-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide,

N⁴ -{2-{methyl[2-(3-pyridinyl)ethyl]amino}-2-oxoethyl}-N⁴-[1(S)-phenylethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide,

N⁴ -{2-[methyl(2-pyridinylmethyl)amino]-2-oxoethyl}-N⁴-[1(S)-phenylethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide,

N⁴ -{2-{methyl[3-(2-pyridinyl)propyl]amino}-2-oxoethyl]-N⁴-[1(S)-phenylethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl-]2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide,

N⁴ -{2-{methyl[2-(2-pyridinyl)ethyl]amino}-2-oxoethyl}-N⁴-(2-pyridinylmethyl)-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide,

N⁴ -{2-{methyl[2-(2-pyridinyl)ethyl]amino}-2-oxoethyl}-N⁴-(3-pyridinylmethyl)-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide,

N⁴ -[(1-methylcyclohexyl)methyl]-N⁴-{2-{methyl[2-(2-pyridinyl)ethyl]amino}-2-oxoethyl}-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide,

N⁴ -[2-(4-hydroxy-1-piperidinyl)-2-oxoethyl]-N⁴ -(cyclohexylmethyl)-N¹-[1(S)-(cyclohexylmethyl)2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide,

N⁴ -{2-[methyl(3-morpholino-3-oxopropyl)amino]-2-oxoethyl]-N⁴-[1(S)-phenylethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide,

N⁴ -{2-{methyl[2-(4-methyl-1-piperazinyl)ethyl]amino}-2-oxoethyl}-N⁴-[1(S)-phenylethyl]-N¹-[1(S)-(cyclo-hexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide.

We claim:
 1. A compound of formula 1

    A--N(R.sup.1)C(O)CH.sub.2 CH(R.sup.2)C(O)--B               (1)

wherein A is R³ R⁴ NC(O)CH₂ wherein (a) R³ is hydrogen or lower alkyland R⁴ is hydrogen, lower alkyl or lower alkyl monosubstituted withlower cycloalkyl or phenyl; or (b) R³ is hydrogen or lower alkyl and R⁴is a heterocyclic ring (hereinafter designated as "Het") which is anunsubstituted, monosubstituted or disubstituted, five- or six-memberedring containing one or two heteroatoms selected from the groupconsisting of N, O and S, and wherein each substituent is lower alkylmonosubstituted with selected independently from the group consisting oflower alkyl, lower alkoxy, halo, amino or lower alkylamino; or (c) R³ islower alkyl and R⁴ is R⁵ R⁶ N-Alk wherein R⁵ and R⁶ each is hydrogen orlower alkyl and Alk is a divalent alkyl radical derived by the removalof two hydrogen atoms of a straight or branched chain hydrocarboncontaining from one to six carbon atoms; or (d) R³ is lower alkyl and R⁴is R^(5A) R^(6A) NCH₂ CH₂ wherein R^(5A) is lower alkyl and R^(6A) ispiperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl,piperazinocarbonyl or 4-(lower alkyl)-1-piperazinylcarbonyl; or (e) R³is lower alkyl and R⁴ is QC(O)(CH₂)_(m) wherein Q is piperidino,morpholino, thiomorpholino, piperazino or 4-(lower alkyl)-1-piperazinyland m is the integer 1 or 2; or (f) R³ is lower alkyl and R⁴ is loweralkoxy; or (g) R³ and R⁴ together with the nitrogen atom to which theyare attached form a pyrrolidino, piperidino, 4-hydroxy-1-piperidinyl,4-[(lower alkoxy)-(lower alkoxy)]-1-piperidinyl, morpholino,thiomorpholino, piperazino or 4-(lower alkyl)-1-piperazinyl; R¹ is(1-8C)alkyl or lower alkyl monosubstituted with lower cycloalkyl,1-(lower alkyl)-(lower cycloalkyl), (bicyclo[2.2.1]hept-2-yl), phenyl,2-(lower alkyl)phenyl, 2-(lower alkoxy)phenyl, 2-halophenyl, 4-(loweralkyl)phenyl, 4-(lower alkoxy)phenyl, 4-halophenyl, 3,5-di(loweralkyl)phenyl, 3,4-methylenedioxyphenyl, 1-naphthyl, 2-naphthyl or Hetwherein Het is as defined in this claim; R² is lower alkyl, (lowercycloalkyl)methyl, benzyl or Het-CH₂ wherein Het is as defined in thisclaim; and B is NHCH(R⁷)CH(OH)--Z wherein R⁷ is lower alkyl, (lowercycloalkyl)methyl, benzyl, [4-(lower alkyl)phenyl]methyl, [4-(loweralkoxy)phenyl]methyl, or (4-halophenyl)methyl, and Z is lower alkyl,lower cycloalkyl, (lower cycloalkyl)methyl, C(O)OR⁸ wherein R⁸ is loweralkyl, the radical of formula 2 ##STR3## wherein R⁹ is lower alkyl andR¹⁰ and R¹¹ each is hydrogen or lower alkyl,[(1-methyl-1H-tetrazol-5-yl)thio]methyl or CH(OH)R¹² wherein R¹² islower alkyl or lower cycloalkyl, with the provisos (1) that theasymmetric carbon atom bearing R⁷ has the (S) configuration, (2) thatwhen Z is lower alkyl, lower cycloalkyl, (lower cycloalkyl)methyl or theradical of formula 2 as defined in this claim then the asymmetric carbonatom bearing the hydroxyl in the NHCH(R⁷)CH(OH) radical has the (S)configuration, (3) that when Z is C(O)OR⁸ wherein R⁸ is lower alkyl, orwhen Z is [(1-methyl-1H-tetrazol-5-yl)thio]methyl, then the asymmetriccarbon atom bearing the hydroxyl in the NHCH(R⁷)CHOH radical has the (R)configuration, and (4) that when Z is CH(OH)R¹² wherein R¹² is loweralkyl or lower cycloalkyl, the asymmetric carbon atoms bearing thehydroxyls in the NHCH(R⁷)CH(OH) and Z radicals have respectively the (R)and (S) configuration; with the additional proviso that the carbon atombearing R² has the (R) configuration, except when R² is CH₂ -Het whereinHet has a nitrogen atom at the point of attachment, and/or Het containsa sulfur atom next to the atom (C or N) at the point of attachment, ofthe Het to the methylene (CH₂), then in the instance of this exceptionthe carbon atom bearing R² has the (S) configuration; or atherapeutically acceptable acid additional salt thereof.
 2. A compoundas claimed in claim 1 where in A is R³ R⁴ NC(O)CH₂ wherein(a) R³ islower alkyl and R⁴ is lower alkyl or lower alkyl monosubstituted withphenyl; or (b) R³ is lower alkyl and R⁴ is a lower alkyl monosubstitutedwith Het wherein Het is as defined in claim 1; (c) R³ is lower alkyl andR⁴ is R⁵ R⁶ N-Alk wherein R⁵ and R⁶ each is lower alkyl and Alk is asdefined in claim 1; (d) R³ is lower alkyl and R⁴ is R^(5A) R^(6A) NCH₂CH₂ wherein R^(5A) is lower alkyl and R^(6A) is piperidinocarbonyl,morpholinocarbonyl or 4-methyl-1-piperazinylcarbonyl; or (e) R³ is loweralkyl and R⁴ is 2-morpholino-2-oxoethyl, 3-morpholino-3-oxopropyl or3-(4-methyl-1-piperazinyl)-3-oxopropyl; or (f) R³ is lower alkyl and R⁴is lower alkoxy; or (g) R³ and R⁴ together with the nitrogen atom towhich they are attached form a pyrrolidino, piperidino,4-hydroxypiperidinyl, 4-(methoxymethoxy)-1-piperidinyl, morpholino,thiomorpholino or 4-methyl-1-piperazinyl; R¹ is (1-8C)alkyl or loweralkyl monosubstituted with lower cycloalkyl, 1-(lower alkyl)-(loweralkyl), (bicyclo[2.2.1]hept-2-yl)phenyl, 2-methyl-phenyl,2-fluorophenyl, 4-methylphenyl, 4-methoxy-phenyl, 4-chlorophenyl,4-fluorophenyl, 3,5-dimethylphenyl, (3,4-methylenedioxy)phenyl,1-naphthyl, 2-naphthyl or Het wherein Het is as defined hereinabove; R²is lower alkyl, (lower cycloalkyl)methyl, benzyl,1H-imidazol-2-ylmethyl, 1H-imidazol-4-ylmethyl,(1-methyl-1H-imidazolyl-4-yl)methyl, 2-thienylmethyl, 2-oxazolylmethyl,4-oxazolylmethyl, 2-thiazolylmethyl, 4-thiazolylmethyl,(2-methyl-4-thiazolyl)methyl, (2-amino-4-thiazolyl)methyl,[2-(methylamino)-4-thiazolyl]methyl, 2-pyridinylmethyl or3-pyridinylmethyl; and B is defined in claim 1;or a therapeuticallyacceptable acid addition salt thereof.
 3. A compound as claimed in claim1 selected from the group consisting of:N⁴ -benzyl-N⁴-(2-morpholino-2-oxoethyl)-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-(cyclopropylmethyl)butanediamide,N⁴ -benzyl-N⁴ -[2-(dimethylamino)-2-oxoethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-(cyclopropylmethyl)butanediamide,N⁴ -[2-(dimethylamino)-2-oxoethyl]-N⁴ -(2-phenylethyl)-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-(cyclopropylmethyl)butanediamide,N⁴ -[2-(dimethylamino)-2-oxoethyl]-N⁴ -(3-phenyl-propyl)-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-(cyclopropylmethyl)butanediamide,N⁴ -benzyl-N⁴ -{2-[methyl(1,1-dimethylethyl)amino]-2-oxoethyl}-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-(cyclopropylmethyl)butanediamide,N⁴ -benzyl -N⁴ -[2-(methylamino)-2-oxoethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-(cyclopropylmethyl)butanediamide,N⁴ -(2-amino-2-oxoethyl)-N⁴ -benzyl-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-(cyclopropylmethyl)butanediamide,N⁴ -benzyl-N⁴ -{2-[(methoxy)methylamino]-2-oxoethyl}-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-(cyclopropylmethyl)butanediamide,N⁴ -[2-(dimethylamino)-2-oxoethyl]-N⁴ -(1-naphthylmethyl)-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-(cyclopropylmethyl)butanediamide,N⁴ -[2-(dimethylamino)-2-oxoethyl]-N⁴ -[(4-methoxyphenyl)methyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-(cyclopropylmethyl)butanediamide,N⁴ -benzyl-N⁴ -[2-(diethylamino)-2-oxoethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-(cyclopropylmethyl)butanediamide,N⁴ -benzyl-N⁴ -{2-{methyl[2-(2-pyridinyl)ethyl]amino}-2-oxoethyl}-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-(cyclopropylmethyl)butanediamide,N⁴ -[2-(dimethylamino)-2-oxoethyl]-N⁴ -(2-pyridinylmethyl)-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-(cyclopropylmethyl)butanediamide,N⁴ -[2-(dimethylamino)-2-oxoethyl]-N⁴ -(3-pyridinylmethyl)-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-(cyclopropylmethyl)butanediamide,N⁴-{2-{methyl{2-[methyl(morpholinocarbonyl)amino]ethyl}amino}-2-oxoethyl}-N.sup.4-[1(S)-phenylethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide,N⁴ -[2-(dimethylamino)-2-oxoethyl]-N⁴ -[1(R)-phenylethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-(cyclopropylmethyl)butanediamide,N⁴ -[2-(dimethylamino)-2-oxoethyl]-N⁴ -[1(S)-phenylethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-(cyclopropylmethyl)butanediamide,N⁴ -[2-(dimethylamino)-2-oxoethyl]-N⁴ -[1(S)-(1-naphthyl)ethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-(cyclopropylmethyl)butanediamide,N⁴ -[2-(dimethylamino)-2-oxoethyl]-N⁴ -[2(R)-phenylpropyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-(cyclopropylmethyl)butanediamide,N⁴ -[2-(dimethylamino)-2-oxoethyl]-N⁴ -[2(S)-phenylpropyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-(cyclopropylmethyl)butanediamide,N⁴ -[2-(dimethylamino)-2-oxoethyl]-N⁴ -(2-methyl-2-phenylpropyl)-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-(cyclopropylmethyl)butanediamide,N⁴ -[1(S)-phenylethyl]-N⁴-{2-{methyl[2-(2-pyridinyl)ethyl]amino}-2-oxoethyl}-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-(cyclopropylmethyl)butanediamide,N⁴ -{2-{[2-(dimethylamino)ethyl]methylamino}-2-oxoethyl}-N⁴-[1(S)-phenylethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-(cyclopropylmethyl)butanediamide,N⁴ -{2-{[2-(diethylamino)ethyl]methylamino}-2-oxoethyl}-N⁴-[1(S)-phenylethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-(cyclopropylmethyl)butanediamide,N⁴ -[2-(dimethylamino)-2-oxoethyl]-N⁴ -[1(S)-phenylethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-propylbutanediamide,N⁴ -benzyl-N⁴ -{2-{methyl[2-(2-pyridinyl)ethyl]amino}-2-oxoethyl}-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-propylbutanediamide,N⁴ -[2-(dimethylamino)-2-oxoethyl]-N⁴ -[1(S)-phenylethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-(1H-imidazol-4-ylmethyl)butanediamide,N⁴ -[2-(dimethylamino)-2-oxoethyl]-N⁴ -[1(S)-phenylethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide,N⁴ -benzyl-N⁴ -{2-{methyl[2-(4-pyridinyl)ethyl]amino}-2-oxoethyl}-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-(cyclopropylmethyl)butanediamide,N⁴ -[2-(dimethylamino)-2-oxoethyl]-N⁴ -[1(S)-phenylethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-(4-thiazolylmethyl)butanediamide,N⁴ -(cyclohexylmethyl)-N⁴ -[2-(dimethylamino)-2-oxoethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-(cyclopropylmethyl)butanediamide,N⁴ -[2-(dimethylamino)-2-oxoethyl]-N⁴ -[1(S)-phenylethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(S)-(2-thienylmethyl)butanediamide,N⁴ -[1(S)-phenylethyl]-N⁴ -(2-morpholino-2-oxoethyl)-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-(cyclopropylmethyl)butanediamide,N⁴ -benzyl-N⁴ -{2-{methyl[2-(2-pyridinyl)ethyl]amino}-2-oxoethyl}-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(S)-(2-thienylmethyl)butanediamide,N⁴ -(cyclohexylmethyl)-N⁴ -(2-morpholino-2-oxoethyl)-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-(cyclopropylmethyl)butanediamide,N⁴ -(cyclohexylmethyl)-N⁴ -[2-(dimethylamino)-2-oxoethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-(4-thiazolylmethyl)butanediamide,N⁴ -(cyclohexylmethyl)-N⁴ -[2-(dimethylamino)-2-oxoethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(S)-(2-thiazolylmethyl)butanediamide,N⁴ -(1(S)-cyclohexylethyl)-N⁴ -[2-(dimethylamino)-2-oxoethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-(cyclopropylmethyl)butanediamide,N⁴ -(cyclohexylmethyl)-N⁴ -(2-morpholino-2-oxoethyl)-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(S)-(2-thiazolylmethyl)butanediamide,N⁴ -[2-(dimethylamino)-2-oxoethyl]-N⁴ -[2(S)-phenylpropyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(S)-(2-thiazolylmethyl)butanediamide,N⁴-benzyl-N⁴ -{2-{methyl[2-(2-pyridinyl)ethyl]amino}-2-oxoethyl}-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(S)-(2-thiazolylmethyl)butanediamide,N⁴ -[2-(dimethylamino)-2-oxoethyl]-N⁴ -[1(S)-phenylethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(S)-hydroxy-2-(1,5,5-trimethyl-2-oxopyrrolidin-3(S)-yl)ethyl]-2(R)-(cyclopropylmethyl)butanediamide,N⁴ -[2-(dimethylamino)-2-oxoethyl]-N⁴ -[1(S)-phenylethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-(3-cyclopropylpropyl)]-2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide,N⁴ -[2-(dimethylamino)-2-oxoethyl]-N⁴ -[1(S)-phenylethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(S)-hydroxy-2-(1,5,5-trimethyl-2-oxopyrrolidin-3(S)-yl)ethyl]-2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide,N⁴ -[2-(dimethylamino)-2-oxoethyl]-N⁴ -[1(S)-phenylethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R)-hydroxy-3-(1-methylethoxy)-3-oxopropyl]-2(R)-[2-amino-4-thiazolyl)methyl]butanediamide,N⁴ -(cyclohexylmethyl)-N⁴-{2-{methyl-[2-(2-pyridinyl)ethyl]amino}-2-oxoethyl}-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-(cyclopropylmethyl)butanediamide,N⁴ -(cyclohexylmethyl)-N⁴ -[2-(dimethylamino)-2-oxoethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-[(2-methyl-4-thiazolyl)methyl]butanediamide,N⁴ -(cyclohexylmethyl)-N⁴ -[2-(dimethylamino)-2-oxoethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide,N⁴ -(cyclohexylmethyl)-N⁴ -(2-morpholino-2-oxoethyl)-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide,N⁴ -(cyclohexylmethyl)-N⁴-{2-{methyl[2-(2-pyridinyl)ethyl]amino}-2-oxoethyl}-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide,N⁴ -[2-(dimethylamino)-2-oxoethyl]-N⁴ -[2-(2-pyridinyl)ethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-(cyclopropylmethyl)butanediamide,N⁴ -benzyl-N⁴ -[2-(dimethylamino)-2-oxoethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide,N⁴ -benzyl-N⁴ -{2-{methyl[2-(2-pyridinyl)ethyl]amino}-2-oxoethyl}-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-(4-thiazolylmethyl)butanediamide,N⁴ -[2-(dimethylamino)-2-oxoethyl]-N⁴ -[1(S)-phenylethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(S)-(2-thiazolylmethyl)butanediamide,N⁴ -(cyclohexylmethyl)-N⁴ -[2-(dimethylamino)-2-oxoethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-(phenylmethyl)butanediamide,N⁴ -{{1(S),2(R),4(S)- and1(R),2(S),4(R)-{bicyclo[2.2.1]hept-2-yl}methyl}-N⁴-[2-(dimethylamino)-2-oxoethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-(4-thiazolylmethyl)butanediamide,N⁴ -benzyl-N⁴ -{2-{methyl[2-(2-pyridinyl)ethyl]amino}-2-oxoethyl}-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide,N⁴ -(cyclohexylmethyl)-N⁴ -[2-(dimethylamino)-2-oxoethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-(3-pyridinylmethyl)butanediamide,N⁴ -(cyclohexylmethyl)-N⁴ -(2-morpholino-2-oxoethyl)-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-(3-pyridinylmethyl)butanediamide,N⁴ -[2-(dimethylamino)-2-oxoethyl]-N⁴ -(2-phenylethyl)-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide,N⁴ -[2-(dimethylamino)-2-oxoethyl]-N⁴ -[2(S)-phenylpropyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide,N⁴ -{2-[4-(methoxymethoxy)piperidin-yl]-2-oxoethyl}-N⁴-[cyclohexyl-methyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-[(2-amino-4-thiazolyl)methyl]butanedamide,N⁴ -[1(S)-cyclohexylethyl]-N⁴-{2-{methyl[2-(2-pyridinyl)ethyl]amino}-2-oxoethyl}-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide,N⁴ -[2-(dimethylamino)-2-oxoethyl]-N⁴ -(2-pyridinylmethyl)-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide,N⁴ -(cyclohexylmethyl)-N⁴-{2-{methyl[2-(2-pyridinyl)ethyl]amino}-2-oxoethyl}-N¹-{1(S)-(cyclohexylmethyl)-2(R)-hydroxy-3-[(1-methyl-1H-tetrazol-5-yl)-thio]propyl}-2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide,N⁴ -(cyclohexylmethyl)-N⁴-{2-{methyl[2-(2-pyridinyl)ethyl]amino}-2-oxoethyl}-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-(3-pyridinylmethyl)butanediamide,N⁴ -(cyclohexylmethyl)-N⁴ -(2-morpholino-2-oxoethyl)-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-(2-pyridinylmethyl)butanediamide,N⁴ -(cyclohexylmethyl)-N⁴ -[2-(dimethylamino)-2-oxoethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-(2-pyridinylmethyl)butanediamide,N⁴ -(cyclopentylmethyl)-N⁴ -[2-(dimethylamino)-2-oxoethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-(3-pyridinylmethyl)butanediamide,N⁴ -(cycloheptylmethyl)-N⁴ -[2-(dimethylamino)-2-oxoethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-(3-pyridinylmethyl)butanediamide,N⁴ -(cyclopentylmethyl)-N⁴-{2-{methyl[2-(2-pyridinyl)ethyl]amino}-2-oxoethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide,N⁴ -{2-{methyl[2-(2-pyridinyl)ethyl]-amino}-2-oxoethyl}-N⁴-(2-thienylmethyl)-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide,N⁴ -[2-(dimethylamino)-2-oxoethyl]-N⁴ -[(3,5-dimethylphenyl)methyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide,N⁴ -(cyclohexylmethyl)-N⁴-{2-{methyl[2-(2-pyridinyl)ethyl]amino}-2-oxoethyl}-N¹-[1(S)-(cyclohexylmethyl)-2(R)-hydroxy-3-(1-methylethoxy)-3-oxopropyl]-2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide,N⁴-{2-{methyl[2-(2-pyridinyl)ethyl]amino}-2-oxoethyl}-N⁴-[1(S)-phenylethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide,N⁴ -(cyclohexylmethyl)-N⁴-{2-{methyl[2-(3-pyridinyl)ethyl]amino}-2-oxoethyl}-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide,N⁴ -(cyclohexylmethyl)-N⁴-{2-{methyl[2-(2-pyridinyl)ethyl]amino}-2-oxoethyl}-N¹-[1(S)-(cyclohexylmethyl)-2(S)-hydroxy-5-methylhexyl]-2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide,N⁴ -(cycloheptylmethyl)-N⁴ -[2-(dimethylamino)-2-oxoethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide,N⁴ -(2-furanylmethyl)-N⁴-{2-{methyl-[2-(2-pyridinyl)ethyl]amino}-2-oxoethyl}-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-[(2-amino-4-thiazolyl)-methyl]butanediamide,N⁴ -(cyclopentylmethyl)-N⁴ -(2-morpholino-2-oxoethyl)-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide,N⁴ -(cycloheptylmethyl)-N⁴-{2-{methyl[2-(2-pyridinyl)ethyl]amino}-2-oxoethyl}-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide,N⁴ -[(2-fluorophenyl)methyl]-N⁴-{2-{methyl[2-(2-pyridinyl)ethyl]amino}-2-oxoethyl}-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide,N⁴ -(cyclohexylmethyl)-N⁴-{2-{methyl{2-[methyl(morpholinocarbonyl)amino]ethyl}amino}-2-oxoethyl}-N.sup.1-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide,N⁴ -(2-ethylbutyl)-N⁴-{2-{methyl[2-(2-pyridinyl)ethyl]amino}-2-oxoethyl}-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide,N⁴ -(cyclopentylmethyl)-N⁴ -[2-(dimethylamino)-2-oxoethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide,N⁴ -{2-{methyl[2-(2-pyridinyl)ethyl]amino}-2-oxoethyl}-N⁴-(2-thiazolylmethyl)-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide,N⁴ -(2-cyclopentylethyl)-N⁴-{2-{methyl[2-(2-pyridinyl)ethyl]amino}-2-oxoethyl}-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide,N⁴ -{2-{methyl[2-(2-pyridinyl)ethyl]amino}-2-oxoethyl}-N⁴-[(3-methyl-2-thienyl)methyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide,N⁴ -(3-furanylmethyl)-N⁴-{2-{methyl-[2-(2-pyridinyl)ethyl]amino}-2-oxoethyl}-N⁴-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide,N⁴ -(cyclohexylmethyl)-N⁴-{2-[methyl-(2-morpholinoethyl)amino]-2-oxoethyl}-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide,N⁴ -{2-{methyl[2-(2-pyridinyl)ethyl]amino}-2-oxoethyl}-N⁴-(1-propylbutyl)-N¹-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide,N⁴ -{2-{methyl[2-(2-pyridinyl)ethyl]amino}-2-oxoethyl}-N⁴-(2-propylpentyl)-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide,and N⁴ -{2-[methyl (2-morpholinoethyl)amino]-2-oxoethyl}-N⁴-[1(S)-phenylethyl]-N¹-[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]-2(R)-[(2-amino-4-thiazolyl)methyl]butanediamide.4. A pharmaceutical composition comprising a compound as claimed inclaim 1, or a therapeutically acceptable acid addition salt thereof, anda pharmaceutically acceptable carrier.
 5. A method for treating reninassociated hypertension in a mammal which comprises administeringthereto a blood pressure-lowering effective amount of a compound offormula 1, or a therapeutically acceptable acid addition salt thereof,as defined in claim
 1. 6. A compound as claimed in claim 2 wherein A isR³ R⁴ NC(O)CH₂ whereinR³ is methyl, ethyl or propyl and R⁴ is methyl,ethyl, propyl, 1,1-dimethylethyl, 2-(dimethylamino)ethyl,2-(diethylamino)ethyl, or Het-(CH₂)n wherein Het is 2-pyrrolyl,2-furanyl, 2-thienyl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, 2-isoxazolyl,2-thiazolyl, 4-thiazolyl, 2-amino-4-thiazolyl, morpholino,4-methyl-1-piperazinyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl or2-pyrimidinyl and n is the integer 1, 2 or 3; or R³ is methyl and R⁴ is2-[methyl(morpholinocarbonyl)amino]ethyl or2-{methyl[(4-methyl-1-piperazinyl)carbonyl]amino}-ethyl; or R³ is methyland R⁴ is 3-morpholino-3-oxopropyl or3-(4-methyl-1-piperazinyl)-3-oxopropyl; or R³ is methyl and R⁴ ismethoxy; or R³ and R⁴ together with the nitrogen to which they areattached form a pyrrolidino, piperidino, 4-hydroxy-1-piperidinyl,4-(methoxymethoxy)-1-piperidinyl, morpholino or 4-methyl-1-piperazinyl;R¹ is 2-methylpropyl, 2-ethylbutyl, 1-propylbutyl, 2-propylpentyl,cyclopentylmethyl, 2-cyclopentyl-ethyl, cyclohexylmethyl,(S)-1-cyclohexylethyl, 2-cyclohexylethyl, cycloheptylmethyl,(1-methylcyclohexyl)methyl, (1-methylcycloheptyl)methyl,(bicyclo[2.2.1]hept-2-yl)methyl, benzyl, (S)-1-phenylethyl,2-phenylethyl, (R or S)-2-phenylpropyl, 2-methyl-2-phenylpropyl,3-phenylpropyl, (2-fluorophenyl)methyl, (2-methylphenyl)methyl,(4-methoxyphenyl)methyl, (4-chlorophenyl)methyl, (4-fluorophenyl)methyl,(3,5-dimethylphenyl)methyl, 1-naphthylmethyl, (S)-[1-(1-naphthyl)ethyl],2-naphthylmethyl, 2-pyrrolylmethyl, 1H-imidazol-2-yl-methyl,1H-imidazol-4-ylmethyl, 2-pyridinylmethyl, 3-pyridinylmethyl,2-furanylmethyl, 3-furanylmethyl, 2-thienylmethyl,(3-methyl-2-thienyl)methyl, 2-oxazolylmethyl, 4-oxazolylmethyl,2-thiazolylmethyl or (2-amino-4-thiazolyl)methyl; R² is propyl,2-methylpropyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexyl-methyl,benzyl, 1H-imidazol-2-ylmethyl, 1H-imidazol-4-ylmethyl,(1-methyl-1H-imidazol-4-yl)methyl, 2-thienylmethyl, 2-oxazolylmethyl,4-oxazolylmethyl, 2-thiazolylmethyl, 4-thiazolylmethyl,(2-methyl-4-thiazolyl)methyl, (2-amino-4-thiazolyl)-methyl,[2-(methylamino)-4-thiazolyl]methyl, 2-pyridinylmethyl or3-pyridinylmethyl; and B is[1(S)-(2-methylpropyl)-2-(S)-hydroxy-5-methylhexyl]amino,[1(S)-(cyclohexylmethyl)-2(S)-hydroxy-5-methylhexyl]amino,{1(S)-[(4-methoxylphenyl)methyl]-2(S)-hydroxy-5-methylhexyl}amino,[1(S)-(cyclohexylmethyl)-2(S)-hydroxy-4-methylpentyl]amino,[1(S)-(cyclohexylmethyl)-2(S)-hydroxy-(3-cyclopropyl propyl)]-amino,[1(S)-(2-methylpropyl)-2(R), 3(S)-dihydroxy-5-methylhexyl]amino,[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]amino,{1(S)-[(4-methoxyphenyl)methyl]-2(R),3(S)-dihydroxy-5-methylhexyl}amino,[1(S)-(2-methylpropyl)-2(R),3(S)-dihydroxy-(3-cyclopropylpropyl)]amino,[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-(3-cyclopropylpropyl)]amino,[1(S)-(phenylmethyl)-2(R),3(S)-dihydroxy-(3-cyclopropylpropyl)]amino,{1(S)-[(4-methoxyphenyl)methyl]-2(R),3(S)-dihydroxy-3-cyclopropylpropyl}-amino,[1(S)-(cyclohexylmethyl)-2(R)-hydroxy-3-(1-methylethoxy)-3-oxopropyl]amino,[1(S)-(cyclohexylmethyl)-2(S)-hydroxy-2-(1,5,5-trimethyl-2-oxo-pyrrolidin-3(S)-yl)ethyl]aminoor{1(S)-(cyclohexylmethyl)-2(R)hydroxy-3-[(1-methyl-1H-tetrazol-5-yl)thio]propyl}amino;or a therapeutically acceptable acid addition salt thereof.
 7. Acompound as claimed in claim 6 wherein A is R³ R⁴ NC(O)CH₂ wherein R³ ismethyl and R⁴ is methyl, 2-(dimethylamino)ethyl, 2-(diethylamino)ethyl,2-(2-pyrrolyl)ethyl, 2-(2-furanyl)ethyl, 2-(1H-imidazol-2-yl)ethyl,2-(1H-imidazol-4-yl)ethyl, 2-(2-thiazolyl)ethyl, 2-morpholinoethyl,2-(2-pyridinyl)-ethyl, 2-(3-pyridinyl)ethyl, 2-(4-pyridinyl)ethyl or2-(2-pyrimidinyl)ethyl; or R³ is methyl and R⁴ is2-[methyl(morpholinocarbonyl)amino]ethyl; or R³ is methyl and R⁴ ismethoxy; or R³ and R⁴ together with the nitrogen atom to which they areattached form a pyrrolidino, piperidino, 4-hydroxy-1-piperidinyl,4-(methoxymethoxy)-1-piperidinyl, morpholino or 4-methyl-1-piperazinyl;R¹ is 2-ethylbutyl, 1-propylbutyl, 2-propylpentyl, cyclopentylmethyl,2-cyclopentylethyl, cyclohexylmethyl, (S)-1-cyclohexylethyl,cycloheptylmethyl, (bicyclo[2.2.1]hept-2-yl)methyl, benzyl,(S)-1-phenylethyl, 2-phenyl-ethyl, (S)-2-phenylpropyl,(R)-2-phenylpropyl, (2-fluorophenyl)methyl, (2-methylphenyl)methyl,(3,5-dimethylphenyl)methyl, 1-naphthylmethyl, 2-furanylmethyl,3-furanylmethyl, 2-thienylmethyl, (3-methyl-2-thienyl)methyl or2-thiazoylmethyl; R² is propyl, cyclopropylmethyl,1H-imidazol-4-ylmethyl, (1-methyl-1H-imidazol-4-yl)methyl,2-thienylmethyl, 2-oxazolylmethyl, 4-oxazolylmethyl, 2-thiazolylmethyl,4-thiazolylmethyl, (2-methyl-4-thiazolyl)methyl or(2-amino-4-thiazolyl)methyl; and B is[1(S)-(cyclohexylmethyl)-2(S)-hydroxy-5-methylhexyl]amino,[1(S)-(cyclohexylmethyl)-2(S)-hydroxy-(3-cyclopropylpropyl)]amino,[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-(3-cyclopropylpropyl)]amino,[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]amino,[1(S)-(cyclohexylmethyl)-2(R)-hydroxy-3-(1-methylethoxy)-3-oxopropyl]aminoor[1(S)-(cyclohexylmethyl)-2(S)-hydroxy-2-(1,5,5-trimethyl-2-oxopyrrolidin-3(S)-yl)ethyl]-amino;or a therapeutically acceptable acid addition salt thereof.